Functionalized organolithium reagents in the synthesis of chiral ligands for catalytic enantioselective addition of diethylzinc to aldehydes

Polyhedron 45 (2012) 126–143

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Polyhedron

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Functionalized organolithium reagents in the synthesis of chiral ligands

for catalytic enantioselective addition of diethylzinc to aldehydes

Georgi M. Dobrikov ^a, Irena Philipova ^a, Rositsa Nikolova ^b, Boris Shivachev ^b, Angel Chimov ^a,

Vladimir Dimitrov ^a,

⇑

^aInstitute of Organic Chemistry with Center of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str. 9, BG-1113 Soﬁa, Bulgaria

^bInstitute of Mineralogy and Crystallography ‘‘Acad. Ivan Kostov’’, Bulgarian Academy of Sciences, Acad. G. Bonchev Str. 107, BG-1113 Soﬁa, Bulgaria

a r t i c l e i n f o

a b s t r a c t

Article history:

Series of functionalized organolithium compounds were prepared and added to chiral bicyclic ketones

(1R-(+)-camphor analogue 2 and 1R-(ꢀ)-fenchone 3), resulting in the preparation of a small ‘‘library’’

of chiral aminoalcohols able to serve as ligands in metal mediated asymmetric synthesis. The conﬁgura-

tion of the chiral ligands was approved by applying advanced NMR experiments. The absolute conﬁgura-

tions of 1,2-disubstituted planar chiral ferrocene-based aminoalcohols 15, 18 and 19 were determined by

means of NMR experiments and conﬁrmed by X-ray crystallography. The new chiral ligands were tested

as pre-catalysts for the addition of diethyl zinc to benzaldehyde. The reactions proceeded with excellent

conversions and a moderate degree of enantioselectivity.

Received 18 April 2012

Accepted 12 June 2012

Available online 22 July 2012

Keywords:

Functionalized organolithiums

Chiral ligands

Absolute conﬁguration

Diethyl zinc

1. Introduction

In the present paper we are applying an organometallic ap-

proach to obtain N- and S-functionalized hydroxy-camphane

The considerable interest in the synthesis and application of

new enantiomerically pure b-, - and d-aminoalcohols by utilizing

derivatives of type A and B (Scheme 1) that possess a similar sub-

stitution at C-1 and C-3 of the bicyclic skeleton, but different ste-

reochemistry at C-2, realized through the different exo/endo-

selectivity of the addition of organolithiums to compounds 2 and

3. Chiral compounds of type of A and B are versatile ligands for di-

verse metal catalyzed transformations and they could be employed

in applications beyond the organozinc additions used to test them

in the present work.

c

different sources of chirality has been an obvious result of their

efﬁciency as pre-catalysts for enantioselective addition of diorg-

anozinc compounds to aldehydes, discovered ﬁrst by Oguni and

Omi [1]. The phenomenon of chirality ampliﬁcation (the non-linear

relationship between the enantiomeric purity of the ligand used

and the enantiomeric excess of the product obtained) has attracted

particular interest and has been studied in detail by Noyori [2]

with the example of N,N-dimethylaminoisoborneol (DAIB). In re-

cent years, a large number of aminoalcohols structurally based

on the bicyclic camphane core have been synthesized using cam-

phor [3], fenchone [3b,4], camphor-10-sulfonamide [5] and similar

chiral sources [6] as the starting materials. The variation of the

substituents attached to the camphane skeleton allows data collec-

tion to study the inﬂuence of the ligand structure on the degree

and sense of enantioselectivity.

2. Results and discussion

2.1. Synthesis of chiral aminoalcohols and analogues by addition of

functionalized organolithiums to bicyclic ketones

For the planned addition reactions, the commercially available

1R-(+)-camphor 1 was transformed into the ketone 2 applying a

known procedure [8a,8c] (Scheme 1). Ketone 2 has been rarely

used for transformations [8b–e]. To the best of our knowledge,

addition reactions of organometallics to 2 have not been studied.

Only the reduction with LiAlH₄leading to the corresponding iso-

borneol analogue has been described [8c]. A set of organolithium

reagents was selected to perform addition reactions to these ke-

tones, leading to dimethylaminoalcohols (with reagents 4–6, 12)

and alcohols containing an N-heterocyclic moiety (with reagents

7, 13–14), which in the case of 13 and 14 possess an additional

Over the few past years, we have been interested in the utiliza-

tion of (+)-camphor and (ꢀ)-fenchone within the addition reactions

of functionalized organometallic reagents, leading to various ami-

noalcohols [3a,3b,7] showing, in several cases, high efﬁciency as

pre-catalysts to form in situ organozinc complexes that are able to

provide enantioselective addition of diethylzinc to aldehydes.

⇑

Corresponding author.

E-mail address: vdim@orgchm.bas.bg (V. Dimitrov).

http://dx.doi.org/10.1016/j.poly.2012.06.090

G.M. Dobrikov et al. / Polyhedron 45 (2012) 126–143

127

13

14

12

18

11

3

4

15

5

8

17 16

9

7

6

2

1

10

3'

1'

4'

2

2'

7'

1'

6'

5'

2'

3'

2

Scheme 1. The addition of organolithiums to

diastereoselective manner, leading to products of type A and

2

and

3

proceeds in

a

highly

1'

B with deﬁned

2'

stereochemistries.

2

7'

6'

3'

4'

5'

1'

Me₂N-group (Schemes 2 and 3). The organolithium reagents were

prepared or generated in situ by using known or modiﬁed pub-

lished procedures [9–17].¹

2'

3'

4'

6'

Addition of organolithium 4 [9] occurred in hexane at room

temperature leading to aminoalcohol 8, isolated in excellent yield

(Scheme 2). In this case the assistance of anhydrous CeCl₃was

not necessary compared with previously published results [3b].

The reaction of 5 [10] and 2 was performed in hexane/Et₂O at room

temperature, with the formation of 9 in good yield. The addition of

the in situ generated 6 [11] to 2 occurs in a low yield (in hexane/

Et₂O). The similar addition of 6 to (ꢀ)-fenchone (3) was also low

yielding and an inseparable mixture of the corresponding endo/

exo fenchol isomers was formed in this case (the ratio of both dia-

stereoisomers was determined by NMR as 8:1, without unambigu-

ous identiﬁcation). Organolithium reagent 7, possessing low

thermal stability, was generated in situ at ꢀ60 °C [12] and the addi-

tion was performed at the same temperature to obtain 11 in good

yield. Similar results have been published for the addition of 7 to

(+)-camphor [18].

The addition of reagents 12–14 to ketones 2 and 3 is presented

in Scheme 3. The 1,2-disubstituted ferrocenyllithium compound 12

was formed and used as a racemate in respect of the chirality plane

[13]. Therefore after addition of 12 to 2, the formation of two dia-

stereoisomers is to be expected, provided only endo-addition oc-

curs. Remarkably, only one diastereoisomer, 15, was observed

and isolated. No experimental evidence for the formation of other

diastereoisomers could be obtained. Compound 15 was identiﬁed

as the endo-addition product (for the conﬁguration determination

see discussion below). Additionally, 60% of the N,N-dimethylami-

nomethyl-ferrocene used to generate 12 was recovered after per-

forming the addition reaction, followed by aqueous work-up

procedure (see Section 4). Therefore, these results indicate that

only one of the planar chiral enantiomers of 12 took part in the

addition reaction, probably due to steric reasons. This suggestion

is strongly supported by the results of the addition reaction of 12

to 3 in respect of the lower steric hindrance in this case during

the course of the nucleophilic attack. The reaction of 12 and 3 fur-

nished the expected two diastereoisomers 18 and 19 in respect of

the chirality plane and as a result of exo-addition (78% overall yield,

ratio 18:19 = 1:2). It should be pointed out that in fact the normal

addition of nucleophiles to bicyclo [2.2.1]-heptan-2-ones with re-

spect to the stereoselectivity is exo due to the signiﬁcant repulsion

caused by the endo-protons. However, the presence of the methyl

group at the C-7 position in the case of 2 executes additional

hindrance, forcing reagent 12 to add against the repulsion of the

7'

5'

Scheme 2. Addition of organolithiums 4–7 to the camphor analogue 2.

endo-protons. The application of organolithiums 13 [14] and 14¹

provided, in the case of 2, products 16 and 17, and in case of 3, com-

pounds 20 and 21 respectively, isolated in moderate yields.

For the synthesis of b-heteroatom functionalized derivatives of

type B (Scheme 1), the organolithium reagents 22a–d [15], 23a–c

[15] and 24–27 [15–17] were prepared in situ from the correspond-

ing heterocycles [19–21] and added to ketone 3 (Scheme 4). The

products 28–34 were isolated in moderate to excellent yields as

single diastereoisomers (see Section 4) as a consequence of the ex-

pected exo-addition selectivity. In the case of 2-lithio-thiophene

(26), small amounts of the bis-substituted derivative 33 were iso-

lated. This is obviously a result of the formation of 2,5-dilithio-thi-

ophene during the lithiation of thiophene with n-BuLi. The

addition reactions of reagents 22–27 to ketone 2 were abandoned

because of the discouraging enantioselectivities, achieved with

products 28–34 applied as ligands for the addition of Et₂Zn to

benzaldehyde (see below).

For the synthesis of c-aminoalcohols, the reagent LiCH₂CN (gen-

erated in situ from n-BuLi and CH₃CN) was added to ketones 2 and

3 (Scheme 5). The addition reaction was performed at ꢀ78 °C in

THF to give the compounds 35 and 36, respectively, in excellent

yields, which were then reduced quantitatively to the correspond-

ing aminoalcohols 37 and 38 (the synthesis of 36 and 38 has been

previously described [3a]). Compounds 37 and 38 were the starting

materials for the preparation of the dialkylamino derivatives 39–

43, obtained in moderate to excellent yields using a standard pro-

cedure (RX/K₂CO₃in reﬂuxing THF/water). Surprisingly, an attempt

to prepare the N,N-dimethyl substituted aminoalcohol from 37

using HCHO/HCOOH (Eschweiler–Clarke procedure) led, under

the reaction conditions, to a new undesired product, assigned as

the heterocyclic derivative 44.

The structures of the new chiral compounds were established by

NMR experiments and mass spectra. The unambiguous assignment

1

To best of our knowledge there is no published procedure for the preparation of

reagent 14, so we have successfully used the in-situ procedure described for the

preparation of 13, starting from 2-(N,N-dimethylamino)-pyridine.

128

G.M. Dobrikov et al. / Polyhedron 45 (2012) 126–143

2

6'

1'

2'

4'

2'

1'

2'

3'

5'

3'

5'

2

3'

5'

4'

R

2

6'

4'

3'

5'

2'

3'

2'

4'

1'

5'

8

4

7

6'

2

5

6

3

9

S

R

2

1

2

10

5'

4'

3'

4'

1'

3'

2'

2

Scheme 3. Addition of organolithiums 12–14 to ketones 2 and 3.

of the ¹H and ¹³C NMR spectra was made on the basis of DEPT,

COSY, HSQC, HMBC and NOESY experiments (see Section 4).

taking into account the known conﬁguration of the corresponding

bicyclic skeleton. For a successful determination of the conﬁgura-

tion, it is sufﬁcient to obtain information concerning the position

of the dimethylamino-methyl-group relative to the C-C-bond con-

necting the substituted Cp-ring and C-2 of the bicyclic skeleton,

and the relative position of the unsubstituted Cp-ring. In the case

of compound 15, the most important proton proximities (pre-

sented by means of arrows) undoubtedly show the location of

the dimethylamino-methyl-group on the side of the spiro-in-

dane-part of the structure. The unsubstituted Cp-ring lies below

the plane of the substituted one (by the presented top view,

Fig. 3) proved by the proton proximity of the 11a-proton and the

protons of the Cp-ring. Consequently, the conﬁguration of 15 is

R_pwith respect to the chirality plane.

For the diastereoisomer 18, the observed NOEs indicate obvi-

ously short distances between the protons of the dimethylamino-

groups and the C-10 methyl group, whereas the C-5⁰proton lies

in close proximity with one of the C-7 protons and the C-8

methyl-protons. The unsubstitute Cp-ring lies on the side of the

C-8 and C-9 methyl groups. These observations are sufﬁcient as a

proof for the S_pconﬁguration of 18 in respect of the chirality plane

and by the known chirality of the bicyclic skeleton. In the case of

diastereoisomer 19, it was possible to determine the position of

the dimethylamino group relative to the C–C-bond between C-2

of the bicyclic skeleton and the Cp-ring (the NOEs are shown with

arrows in Fig. 4). However, no certain data could be obtained about

the relative position of the unsubstituted Cp-group. Therefore, the

R_pconﬁguration of the diastereoisomer 19 was deduced from these

observations and supported by the conﬁguration determined for

18.

2.2. Conﬁguration determination by NMR methods

In all cases the observed endo/exo diastereoselectivities of the

addition reactions to the carbonyl C-atom of ketones 2 and 3 were

excellent as a result of exclusive endo-attack of the organolithium

reagents to 2 and exo-attack to 3, respectively, proved by the NMR

experiments.

The endo-position of the substituents was conﬁrmed by NOESY

spectra through the observed proton proximities of H-atoms from

the corresponding substituent in compounds 8–11, 16, 17, 35 and

37 with the endo-positioned protons of the bicyclic core (Fig. 1).

Furthermore, the H-atom proximities observed by the NOESY spec-

tra have decisively contributed to the unambiguous assignment of

the ¹H and ¹³C signals within the structures synthesized.

The same approach has been applied to conﬁrm the exo-posi-

tion of the substituents in compounds 28–33, 20 and 21 by means

of the NOESY spectra. The most important H-atoms proximities ob-

served and shown in Fig. 2 illustrate undoubtedly the exo-attack

during the addition of the corresponding organolithium reagents

(compare Schemes 3 and 4).

The determination of the conﬁguration of the ferrocene deriva-

tives 15, 18 and 19 was of particular interest, since similar types of

ferrocene compounds are important precursors for asymmetric

catalysis. The NOESY experiments brought extensive information

about the proton neighborhood within the ferrocene derivatives,

allowing the determination of the locations of the protons and

therefore of the individual parts of the molecules relative to each

other. Consequently, the results of this approach also allow the

determination of the absolute conﬁguration of these three com-

pounds in respect of the chirality plane within the ferrocene core,

The conﬁgurations of ferrocene derivatives 15 and 18 suggest a

close proximity of the hydroxyl protons and the N-atoms, and thus

existence of hydrogen bonding.

G.M. Dobrikov et al. / Polyhedron 45 (2012) 126–143

129

tween the mean planes of the cyclopentadienyl rings of 8.9(7)°. An

intramolecular hydrogen bond, O1-H1ꢁꢁꢁN1 (DꢁꢁꢁA distance of

2.831(4) Å), is probably responsible for the observed conformation.

The lack of additional hydrogen bond donors and acceptors pre-

vents the formation of intermolecular hydrogen bonds. However,

a weak intermolecular interaction of the Oꢁꢁꢁꢁꢁ

p type (shortest dis-

tance O1ꢁꢁꢁꢁꢁC7 of the substituted Cp is 3.303 Å) can be detected

(Fig. 6a). The absolute conﬁguration of 15 has been determined

independently as R_p, thus conﬁrming the NMR analysis (see Fig. 3).

Suitable crystals of 18 for X-ray structural analysis were difﬁcult

to obtain. After several recrystallization attempts, crystals of 18

were grown by slow evaporation from CH₂Cl₂/DMSO solution (2/

1.3 v/v) at room temperature. Compound 18 crystallizes in the

non-centrosymmetric group P2₁2₁2₁(SG 19) with one molecule

per asymmetric unit (Table 1). An ^ORTEPview of a molecule of 18 is

shown in Fig. 5b and selected bond distances and bond angles are

given in Tables 2 and 3. The major structural features of 15 and 18

are comparable: similar bond lengths and angles, slightly distorted

Cp–Fe–Cp coordination geometry (rms of 0.007 and 0.011 Å for C1/

C2/C3/C4/C5 and C6/C7/C8/C9/C10 mean planes, respectively; the

angle between the mean planes of the Cp rings is 4.0(6)°). Also in

this case an intramolecular O1–H1ꢁꢁꢁN1 (DꢁꢁꢁA distance of

2.822(3) Å) hydrogen bond is responsible for stabilizing the ob-

served conformation. A weak intermolecular interaction of the

4' 5'

3'

2'

1

1'

2

5'

3

4'

6'

1

3

5'

6'

1

7'

i

6'

5'

4'

6'

7'

8'

7'

6'

3'

9'

7'

2'

5'

4'

3

8'

1

10'

1'

9' 10'

1

8'

11'

10'

9' 10'

11'

12'

1

i

Oꢁꢁꢁꢁꢁ

p type was also detected in 18 between O1 and the p-orbitals

9'

of the unsubstituted Cp ring (shortest O1ꢁꢁꢁꢁꢁC–Cp distance of

3.437 Å) (Fig. 6b). The absolute conﬁguration of 18 has been deter-

mined independently as S_p, conﬁrming the NMR analysis (see Fig. 4).

8'

10'

11'

4'

2'

3'

5'

6'

2.4. Enantioselective addition of Et₂Zn to benzaldehyde

1'

9'

8'

4'

7'

The chiral aminoalcohols and analogues synthesized were tested

as pre-catalysts (3 mol%) for the enantioselective addition of Et₂Zn

to benzaldehyde (Table 4) by use of a standard procedure [28]. In all

cases, the yields of the isolated 1-phenyl-1-propanol were excel-

lent. However, the observed enantioselectivities were low to mod-

erate, and in the case of 15, 18 and 19 no asymmetric induction was

realized. These latter results are surprising since 1,2-disubstituted

ferrocene-based planar chiral aminoalcohols are very efﬁcient

pre-catalysts for enantioselective organo-zinc additions to alde-

hydes [1a]. The d-aminoalcohols 8–11 afforded a similar degree of

enantioselectivity as reported for their (+)-camphor derived ana-

logues [3b]. Therefore the C-3 ‘‘fenchone-like’’ substitution realized

within these compounds did not result in an enantioselectivity

improvement. A comparison of the couples of compounds 16 and

20, 17 and 21, 39 and 42, 40 and 43 leads to the conclusion that

the position of the HO-group has a more signiﬁcant inﬂuence on

the enantioselectivity than the substituents in the 3- and 7-posi-

tions on the bicyclic skeleton – the endo-OH derivatives brought

higher selectivity than the exo-one. The same trend was observed

in the case of compound 41 and its fenchone derived analogue with

a pyrrolidine group instead of an Et₂N-group – 26% ee for 41 and

79% ee for the endo-OH analogue (unpublished results; the synthe-

sis was achieved by a different synthetic approach).

3'

5'

2'

6'

7'

1'

9'

3'

8'

2'

1'

4'

3'

2'

4'

5'

1'

7'

6'

Scheme 4. Addition of organolithiums 22–27 to ketone 3.

2.3. Crystal structure and conﬁguration determination of ferrocene

derivatives 15 and 18 by X-ray crystallography

Crystals of 15 were grown by recrystallization in a 6 ml CHCl₃/

CH₃OH 1:1 v/v solution at room temperature. Compound 15 crys-

tallizes in the non-centrosymmetric group P2₁2₁2₁(SG 19) with

one molecule per asymmetric unit (Table 1). The ^ORTEPplot with

the atomic numbering system of 15 is shown in Fig. 5a and selected

bond distances and bond angles are listed in Tables 2 and 3. The

bond distance and angles of the camphane and spiro-indane moi-

eties are comparable to those observed in other structures

[22,8e,23–26]. The indane ring is almost planar (rms of 0.0348 Å)

although it contains two sp³carbons (C23 and C30). The cyclopen-

tadienyl rings are also nearly planar with rms values of 0.004 and

0.005 Å. The structure of 15 reveals a slightly distorted coordina-

tion geometry of the metal center (Fe) and the cyclopentadienyl li-

gands, with Fe–Cp distances of 1.652(4) and 1.665(4) Å for C4/C5/

C6/C7/C8 and C9/C10/C11/C12/C13, respectively, and an angle be-

3. Conclusions

In conclusion, we have demonstrated a practicable application

of functionalized organolithium reagents for the synthesis of chiral

b-,

c- and d-aminoalcohols and some analogues possessing the

bicyclo-heptane skeleton as the central core. The use of cheap and

readily available sources of chirality makes the presented synthetic

strategies very advantageous. The series of compounds synthesized

were isolated in the diastereoisomeric pure form and were charac-

terized by spectroscopic methods. The conﬁgurations, in respect of

130

G.M. Dobrikov et al. / Polyhedron 45 (2012) 126–143

1'

2'

2

4

2

2'

1'

3'

4'

5'

3'

6'

4'

8'

7'

6'

5'

6'

3' 4'

4'

3'

7'

1'

3'

7'

5' 6'

4'

8'

2'

2

3'

1'

2'

Scheme 5. Addition of cyanomethyl lithium to 2 and 3 and the consequent transformation into aminoalcohols 39–43.

the newly induced chirality, within the compounds synthesized

were determined by applying advanced NMR methods. In the case

of the ferrocene-based derivatives, possessing a chirality plane, the

conﬁgurations determined were proved by means of X-ray crystal-

lography. The application of the compounds prepared as ligands for

enantioselective addition of Et₂Zn to benzaldehyde brought in some

cases an acceptable degree of enantioselectivity.

Na/benzophenone. Hexane was distilled over Na[AlEt₄]. N,N-

dimethylaminoethanol was dried over a molecular sieve (3 Å). Thin

layer chromatography (TLC) was performed on aluminum sheets

pre-coated with Merck Kieselgel 60 F₂₅₄0.25 mm (Merck). Flash col-

umn chromatography was carried out using Silica Gel 60 230–400

mesh (Fluka). Melting temperatures were determined in capillary

tubes on an Electrothermal MEL-TEMP 1102D-230 VAC apparatus

(without corrections). Optical rotation ½a _D²⁰

ꢂ

measurements were

obtained using a Perkin–Elmer 241 polarimeter. The NMR spectra

were recorded at ambient temperature (300 K) on a Bruker

Avance DRX-250 (250.13 MHz for ¹H and 62.90 MHz for ¹³C) and

Bruker Avance II + 600 (600.13 MHz for ¹H and 150.92 MHz and

for ¹³C NMR) spectrometers with TMS as internal standard for

chemical shifts (d, ppm). For the numbering of the C-atoms see

4. Experimental

4.1. Materials and instrumentation

The reactions with organolithiums were carried out in Schlenk

ﬂasks under an argon atmosphere. THF and Et₂O were distilled over

G.M. Dobrikov et al. / Polyhedron 45 (2012) 126–143

131

endo

,

syn

2

1

endo

a,b

endo

a,b

endo

syn

2

Fig. 1. Proton proximities of compounds 8–11, 16, 17, 35 and 37, obtained by

means of NOESY spectra.

Fig. 2. Proton proximities of compounds 28–33, 20 and 21, obtained by means of

NOESY spectra.

Schemes 2–5. ¹H and ¹³C NMR data are reported as follows: chem-

ical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,

br = broad, m = multiplet), integration, identiﬁcation and coupling

constants (Hz). The chemical shifts of the ambiguously assigned sig-

nals in NMR data are marked with an asterisk (Cp stands for cyclo-

pentadienyl). Mass spectra (MS) were recorded on a Hewlett–

Packard 5973A spectrometer at 70 eV EI and are reported as

fragmentation in m/z with relative intensities (%) in parentheses.

Enantiomeric excesses of 1-phenyl-1-propanol were determined

by chiral GC using a Shimadzu 17-A chromatograph (chiral capillary

column: Hydrodex-b-TBDAc, 25 m, 0.25 lm). Elemental analyses

were performed by the Microanalytical service Laboratory of the

Institute of Organic Chemistry, Bulgarian Academy of Science. X-

ray crystallographic analysis: Crystals of (R_p)-15 and (S_p)-18 suit-

able for X-ray analyses were obtained after re-crystallization of

the compounds. Subsequently a crystal of (R_p)-15 or (S_p)-18 was

mounted on a glass capillary and all geometric and intensity data

were taken from that crystal. Diffraction data were collected at

room temperature by the

tion SuperNova Dual four-circle diffractometer equipped with an

Atlas CCD detector using mirror-monochromatized Cu

(k_Cu= 1.5418 Å) and Mo K (k_Mo= 0.7107 Å) radiation from a

x-scan technique, on an Agilent Diffrac-

K

a

micro-focus source. The determination of cell parameters, data inte-

gration, and scaling and absorption corrections were carried out

using the CrysAlis Pro program package [29]. The structures were

solved by direct methods [30] and reﬁned by full-matrix least-

square procedures on F2 [30]. The numbering of atoms in the X-

ray structures (Figs. 5 and 6, Tables 2 and 3) is different from other

numbering. The following starting materials were used (commer-

cially available or prepared according to the literature): n-BuLi 1.6

and 2.5 M solutions in hexane (Aldrich), t-BuLi 1.7 M solution in

Fig. 3. Observed NOEs, allowing the determination of the absolute conﬁguration of

compound 15 (R_p) with respect to the chirality plane.

pentane (Aldrich), (1R)-(+)-camphor (Fluka), (1R)-(ꢀ)-fenchone

(Fluka), acetonitrile (Fluka), ethyliodide (Fluka),

a,

a⁰-dichloro-

o-xylene

(Aldrich),

N,N-dimethylaminopropyl-lithium

[9],

benzylbromide (Fluka), N,N-dimethylbenzyl amine (Fluka),

132

G.M. Dobrikov et al. / Polyhedron 45 (2012) 126–143

Fig. 4. Observed NOEs, allowing the determination of the absolute conﬁguration of compounds 18 (S_p) and 19 (R_p) with respect to the chirality plane.

Table 1

Important crystallographic and reﬁnement details for compounds 15 and 18.

Compound

15

18

Chemical formula

MW

C

₃₁H₃₉FeNO

C₂₃H₃₃FeNO

395.35

497.48

Crystal system, SG

orthorhombic, P2₁2₁2₁

10.1616(4)

11.1554(5)

23.0979(10)

2618.30(19)

4

orthorhombic, P2₁2₁2₁

8.7060(6)

12.8582(8)

18.3465(9)

2053.8(2)

4

a (Å)

b (Å)

c (Å)

V (Å³)

Z

F(000)

1064

1.262

848

1.279

D_calc(Mg m^ꢀ3

)

Radiation/k (Å)

(mm^ꢀ1

T (K)

Cu K

4.78

290(2)

a

/1.5418

Mo K

0.75

290(2)

a/0.7107

l

)

Crystal habit, color

Crystal size (mm)

Diffractometer

prism, yellow

0.24 ꢃ 0.23 ꢃ 0.22

SuperNova, Dual, Cu at zero, Atlas

SuperNova (Cu) X-ray Source

mirror

0.16 ꢃ 0.12 ꢃ 0.12

SuperNova, Dual, Cu at zero, Atlas

SuperNova (Mo) X-ray Source

mirror

10.3974

x scans

Radiation source

Monochromator

Detector resolution,pixels (mm^ꢀ1

Measurement method

)

10.3974

x

scans

Measured reﬂections/reﬂections with I > 2

r

(I)

9344/2775

9157/1914

R_int

0.066

0.184

h_min/h_max(°)

Reﬁnement

Least-squares matrix

3.8/71.6

3.2/28.2

on F²

full

0.078

0.185

1.07

full

0.088

0.248

1.02

R[F²> 2

wR(F²)

S

r

(F²)]

Independent reﬂections

Parameters

4561

313

4224

236

Constraints

0

Primary atom site location

Secondary atom site location

Hydrogen site location

H-atom parameters

Weighing scheme w

structure-invariant direct methods

difference Fourier map

inferred from neighboring sites

constrained

structure-invariant direct methods

difference Fourier map

inferred from neighboring sites

constrained

1/[r

²(F_o²) + (0.0549P)²+ 3.6227P]where P = (F_o²+ 2F²_c)/3

1/[r

²(F²_o) + (0.1038P)²]where P = (F_o²+ 2F²_c)/3

(

D

q

/

r

)

0.001

max

/

_minDq_max(e Å^ꢀ3

)

ꢀ0.37/0.30

0.00171 (18)

Flack H.D. [27]

ꢀ0.011 (10)

ꢀ0.55/0.7

Extinction correction

Absolute structure

Flack parameter

none

Flack H.D. [27]

ꢀ0.09 (6)

N,N-dimethyl-o-toluidine (Aldrich), 2,6-dimethylpyridine (Aldrich),

N,N-dimethylaminomethylferrocene (Alfa-Aeser), 2-dimethylami-

nopyridine (Fluka), 4-dimethylaminopyridine (Fluka), imidazole

(Fluka), N-ethylimidazole (Merck), N-benzylimidazole (Aldrich),

N-phenyl-imidazole (Alfa-Aesar), benzimidazole (Acros), N-methyl-

indole (Aldrich), quinoline (Fluka), thiophene (Fluka), benzothiazole

(Aldrich), N,N-dimethylaminoethanol (Fluka).

4.2. (3R,4R)-3-(3-(dimethylamino)propyl)-4,7,7-trimethyl-1⁰,3⁰-

dihydrospiro[bicyclo[2.2.1]-heptane-2,2⁰-inden]-3-ol (8)

To a stirred solution of N,N-dimethylaminopropyl-lithium 4

(0.137 g, 1.47 mmol) in 10 ml hexane, ketone

2 (0.250 g,

0.98 mmol) was added at room temperature and the reaction mix-

ture was stirred for 4 h (the reaction progress was monitored by

G.M. Dobrikov et al. / Polyhedron 45 (2012) 126–143

133

Fig. 5. ORTEP view of compounds (R_p)-15 (a) and (S_p)-18 (b) with the atomic numbering scheme; ellipsoids are drawn at 50% probability, hydrogen atoms have been omitted

for clarity.

143.16 (s, 1 arom. C), 125.78 (d, 1 arom. C), 125.63 (d, 1 arom.

C), 123.81 (d, 1 arom. C), 122.94 (d, 1 arom. C), 82.75 (s, C-2),

61.73 (t, C-3⁰), 60.43 (s, C-3), 59.04 (d, C-4), 50.09 (s, C-1), 48.78

(s, C-7), 45.17 (q, 2C, N(CH₃)₂), 43.29 (t, C-11), 42.99 (t, C-18),

35.23 (t, C-1⁰), 30.44 (t, C-6), 24.03 (t, C-2⁰), 23.28 (q, C-8), 23.06

(q, C-9), 22.33 (t, C-5), 12.00 (q, C-10).

Table 2

Selected bond lengths for compounds 15 and 18.

Compound 15

Bond lengths (Å)

Compound 18

Bond lengths(Å)

N1—C1

N1—C2

N1—C3

O1—C14

Fe1—C11

Fe1—C12

Fe1—C13

Fe1—C4

Fe1—C5

Fe1—C6

Fe1—C7

Fe1—C8

1.486(8)

1.462(11)

1.477(11)

1.439(7)

2.050(10)

2.023(8)

2.033(9)

2.068(7)

2.106(6)

2.051(8)

2.031(10)

2.036(9)

2.039(9)

2.040(10)

1.516(13)

1.521(14)

1.558(13)

1.594(13)

1.540(15)

1.562(13)

1.603(14)

N1—C11

N1—C12

N1—C13

C14—O1

Fe1—C1

Fe1—C2

Fe1—C3

Fe1—C4

Fe1—C5

Fe1—C6

Fe1—C7

Fe1—C8

Fe1—C9

Fe1—C10

C15—C14

C15—C23

C15—C30

C19—C14

C19—C18

C19—C19A

C19—C20

1.464(13)

1.471(14)

1.467(13)

1.442(10)

2.052(10)

2.057(10)

2.043(10)

2.047(9)

2.007(10)

2.031(10)

2.032(10)

2.018(10)

2.025(9)

2.073(10)

1.627(8)

1.565(8)

1.564(8)

1.548(8)

1.566(9)

1.517(9)

1.566(9)

4.3. (3R,4R)-3-(2-((dimethylamino)methyl)phenyl)-4,7,7-trimethyl-

1⁰,3⁰-dihydrospiro[bicyclo[2.2.1]-heptane-2,2⁰-inden]-3-ol (9)

To a stirred solution of N,N-dimethylbenzylamine (0.390 g,

2.9 mmol) in hexane/Et₂O (5 ml/2 ml) 2.5 M n-BuLi in hexane

(0.8 ml, 2.00 mmol) was added at room temperature and the solu-

tion was reﬂuxed for 3 h. Then 2 (0.350 g, 1.40 mmol) was added at

room temperature and the reaction mixture was stirred for 22 h

(the reaction progress was monitored by TLC). The reaction was

carefully quenched with H₂O and extracted with Et₂O. The organic

extract was dried over anhydrous Na₂SO₄and the solvent

evaporated in vacuo. The crude product was puriﬁed by column

Fe1—C9

Fe1—C10

C18—C19

C19—C19A

C19—C19B

C14—C19

C15—C16

C15—C20

C15—C14

chromatography (U = 20 mm, h = 280 mm, 40 g silica gel, hex-

ane:Et₂O = 4:1), to give 0.383 g, (64%) of 9 as colorless crystals.

Mp 58–60 °C. ½a ²_D⁰

ꢂ

= 0 (c 0.62, CHCl₃). Anal. Calc. for C₂₇H₃₅NO

(389.57): C, 83.24; H, 9.06; N, 3.60. Found: C, 83.18; H, 9.07; N,

3.62%. MS (EI) m/z (rel. int.): 389 (M⁺ꢀ, 73), 344 (97), 246 (47),

233 (39), 163 (100). ¹H NMR (250 MHz, CDCl₃, 300 K) d: 7.72 (d,

1H, 2⁰-H, J = 8.1 Hz), 7.30–7.69 (m, 7H, Ar), 4.01 (d, 1H, 18-H_a, J =

18.0 Hz), 3.53 (d, 1H, 7⁰-H, J = 12.3 Hz), 3.27 (d, 1H, 18-H_b,

J = 18.0 Hz), 3.03 (d, 1H, 11-H_a, J = 18.2 Hz), 2.76 (d, 1H, 11-H_b,

J = 18.2 Hz), 2.50 (d, 1H, 7⁰-H, J = 12.3 Hz), 2.51–2.36 (m, 1H, 6-H_en-

_do), 1.97 (s, 6H, N(CH₃)₂), 1.69–1.57 (m, 4H, 4-H, 5-H, 6-H_exo), 1.54

(s, 3H, 8-H), 1.30 (s, 3H, 10-H), 1.01 (s, 3H, 9-H). ¹³C NMR

(250 MHz, CDCl₃, 300 K) d: 144.79 (s, 1 arom. C), 143.86 (s, 1

arom. C), 142.19 (s, 1 arom. C), 137.42 (s, 1 arom. C), 134.13 (d, 1

arom. C), 130.87 (d, 1 arom. C), 126.59 (d, 1 arom. C), 126.16 (d,

1 arom. C), 126.09 (d, 1 arom. C), 125.70 (d, 1 arom. C), 124.47

(d, 1 arom. C), 123.83 (d, 1 arom. C), 90.93 (s, C-2), 63.84 (t,

C-7⁰), 59.69 (s, C-3), 58.52 (d, C-4), 54.75 (s, C-1), 51.23 (s, C-7),

46.13 (t, C-18), 44.24 (q, 2C, N(CH₃)₂), 41.67 (t, C-11), 31.54 (t,

C-6), 24.84 (q, C-9), 24.60 (q, C-8), 23.69 (t, C-5), 14.62 (q, C-10).

TLC). The reaction was carefully quenched with 2 ml H₂O and ex-

tracted with Et₂O. The organic extract was dried over anhydrous

Na₂SO₄and the solvent evaporated in vacuo. The crude product

was puriﬁed by column chromatography

(U = 20 mm,

h = 280 mm, 20 g silica gel, Et₂O:Et₃N = 100:1), to give 0.270 g,

(80%) of 8 as colorless crystals. Mp 93–94 °C. ½a _D²⁰

ꢂ

= +33.0 (c 0.57,

CHCl₃). Anal. Calc. for C₂₃H₃₅NO (341.27): C, 80.88; H, 10.33; N,

4.10. Found: C, 80.60; H, 10.14; N, 4.11%. MS (EI) m/z (rel. int.):

341 (M⁺ꢀ, 100), 230 (37), 198 (35), 185 (16), 156 (35). ¹H NMR

(250 MHz, CDCl₃, 300 K) d: 7.13–7.04 (m, 4H, Ar), 4.00 (d, 1H, 18-

H_a, J = 16.4 Hz), 3.14 and 3.02 (AB-system, 2H, 11-H, J = 16.4 Hz),

2.77 (d, 1H, 18-H_b, J = 16.4 Hz), 2.12–1.99 (m, 2H, 3⁰-H_a, 1⁰-H_a),

1.94 (s, 6H, N(CH₃)₂), 1.95–1.87 (m, 1H, 3⁰-H_b), 1.66–1.43 (m, 5H,

4-H, 2⁰-H, 6-H_exo, 1⁰-H_b), 1.35 (s, 3H, 8-H), 1.36–1.16 (m, 2H, 5-H_exo

,

6-H_endo), 0.93–0.80 (m, 1H, 5-H_endo), 0.88 (s, 3H, 9-H), 0.85 (s, 3H,

10-H).¹³C NMR (250 MHz, CDCl₃, 300 K) d: 145.00 (s, 1 arom. C),

134

G.M. Dobrikov et al. / Polyhedron 45 (2012) 126–143

Table 3

Selected bond angles for compounds 15 and 18.

Compound 15

Bond angles (°)

Compound 18

Bond angles (°)

C1—C2—C3

C1—C5—C4

C5—C4—C3

C4—C3—C2

C8—C7—C6

C7—C8—C9

C7—C6—C10

C8—C9—C10

O1—C14—C10

O1—C14—C15

O1—C14—C19

C20—C15—C14

C15A—C15—C14

C15A—C15—C16

C15A—C15—C20

C16—C15—C14

C16—C15—C20

C19A—C19—C14

C19A—C19—C19B

C19B—C19—C14

C18—C19—C19A

C18—C19—C19B

N1—C11—C9

106.6(9)

110.9(10)

106.1(11)

108.4(11)

109.0(10)

109.2(9)

108.8(9)

107.6(8)

107.0(6)

110.1(8)

106.3(8)

99.7(8)

114.5(8)

116.9(10)

116.9(9)

106.6(9)

99.9(8)

117.1(8)

105.5(9)

112.5(7)

107.1(8)

111.6(9)

112.5(8)

111.0(8)

109.1(8)

110.1(9)

C6—C5—C4

C6—C7—C8

C7—C6—C5

C7—C8—C4

105.6(6)

107.4(7)

110.5(7)

108.8(7)

108.8(10)

108.7(11)

110.3(4)

106.3(4)

102.9(5)

107.7(6)

102.9(5)

102.1(5)

121.1(5)

113.4(5)

107.1(5)

111.9(6)

104.2(5)

111.9(6)

110.5(5)

107.1(5)

110.1(6)

110.4(6)

111.4(7)

110.8(8)

109.4(6)

C9—C10—C11

C11—C12—C13

O1—C14—C15

O1—C14—C19

O1—C14—C5

C8—C4—C5

O1—C14—C5

C19—C14—C15

C5—C14—C15

C5—C14—C19

C29—C30—C15

C29—C24—C23

C20B—C20—C20A

C29—C24—C23

C16—C15—C23

C29—C30—C15

C24—C29—C30

N1—C1—C4

C11—N1—C12

C11—N1—C13

C13—N1—C12

C2—N1—C1

C2—N1—C3

C3—N1—C1

Compound 15

Torsion angles (°)

Compound 18

Torsion angles (°)

C1—C2—C3—C4

C2—C1—C5—C4

C2—C3—C4—C5

C3—C4—C5—C1

C5—C1—C2—C3

C6—C7—C8—C9

C11—C9—C10—C14

C10—C6—C7—C8

C11—C9—C10—C6

O1—C14—C15—C16

O1—C14—C15—C20

ꢀ0.4(12)

ꢀ1.8(13)

ꢀ0.6(12)

1.5(12)

C1—C4—C5—C14

C1—C4—C5—C6

C1—C4—C8—C7

C4—C5—C6—C7

C4—C8—C7—C6

C10—C9—C13—C12

C10—C11—C12—C13

C11—C12—C13—C9

C12—C11—C10—C9

O1—C14—C5—C4

O1—C14—C5—C6

ꢀ14.0(10)

ꢀ172.5(7)

173.2(7)

0.5(9)

ꢀ0.9(11)

ꢀ0.2(10)

ꢀ1.0(13)

0.7(12)

1.3(13)

ꢀ0.3(12)

20.7(18)

1.8(12)

ꢀ175.4(10)

ꢀ41.7(10)

ꢀ145.2(8)

0.9(11)

ꢀ55.0(7)

99.5(7)

Fig. 6. Three-dimensional arrangement of the molecules in the crystal structures of compounds (R_p)-15 (a) and (S_p)-18 (b). The weak OꢁꢁꢁCp (Oꢁꢁꢁ

p

type) interaction is shown

as a dashed line. Hydrogen atoms not involved in interactions have been omitted for clarity.

4.4. (3R,4R)-3-(2-(dimethylamino)benzyl)-4,7,7-trimethyl-1⁰,3⁰-

dihydrospiro[bicyclo[2.2.1]heptane-2,2⁰-inden]-3-ol (10)

extract was dried over anhydrous Na₂SO₄and the solvent

evaporated in vacuo. The crude product was puriﬁed by column

chromatography (

ane:CH₂Cl₂= 10:1), to give 0.090 g, (22%) of 10 as an oil.

= +72.7 (c 1.08, CHCl₃). Anal. Calc. for C₂₇H₃₅NO (389.57): C,

83.24; H, 9.06; N, 3.60. Found: C, 83.22; H, 9.08; N, 3.59%. MS (EI)

m/z (rel. int.): 389 (M⁺ꢀ, 33), 278 (31), 246 (20), 204 (19), 164

(19), 135 (100). ¹H NMR (600 MHz, CDCl₃, 300 K) d: 7.26 (s, OH),

7.22–7.19 (m, 2H, Ar), 7.14–7.12 (m, 2H, Ar), 7.00 (m, 4H, Ar),

4.00 (d, 1H, 18-H_a, J = 15.3 Hz), 3.30 (d, 1H, 11-H_b, J = 15.7 Hz),

U = 17 mm, h = 380 mm, 20 g silica gel, hex-

To a stirred solution of N,N-dimethyl-o-toluidine (0.178 g,

1.32 mmol) in hexane/Et₂O (5 ml/0.3 ml), 2.5 M n-BuLi in hexane

(0.44 ml, 1.10 mmol) was added at room temperature and the solu-

tion was reﬂuxed for 72 h. Then 2 (0.280 g, 1.10 mmol) was added

at room temperature and the reaction mixture was stirred for 6 h

(the reaction progress was monitored by TLC). The reaction was

carefully quenched with H₂O and extracted with Et₂O. The organic

½ ꢂ

a ²_D⁰

G.M. Dobrikov et al. / Polyhedron 45 (2012) 126–143

135

Table 4

Enantioselective addition of Et₂Zn to benzaldehyde using the ligands synthesized.

4.6. (3R,4R,pS)-3-(2-(N,N-dimethylaminomethyl)ferrocen-yl)-4,7,7-

trimethyl-1⁰,3⁰-dihydrospiro-[bicyclo[2.2.1]heptane-2,2⁰-inden]-3-ol

Yield^a(%)

ee^b(%)

Ligand

Yield^a(%)

ee^b(%)

(15)

Ligand

8

9

99

84

96

99

55

96

84

93

91

97

99

96

88

97

58 (S)

14 (S)

58 (S)

12 (R)

2 (R)

6 (S)

11 (R)

0

28d

29a

29b

29c

30

31

32

33

34

39

40

41

42

99

97

99

97

92

96

59

85

92

99

96

99

30 (S)

50 (S)

44 (S)

52 (S)

18 (R)

34 (S)

4 (R)

16 (R)

46 (S)

10 (S)

3 (R)

To a stirred solution of N,N-dimethylaminomethylferrocene

(0.46 g, 1.89 mmol) in 10 ml hexane, 2.5 M n-BuLi in hexane

(0.76 ml, 1.89 mmol) was added at room temperature and the solu-

tion was stirred for 24 h. Then 2 (0.40 g, 1.57 mmol) was added at

room temperature and the reaction mixture was stirred for 24 h

(the reaction progress was monitored by TLC). The reaction was

carefully quenched with H₂O and extracted with Et₂O. The organic

extract was dried over anhydrous Na₂SO₄and the solvent evapo-

rated in vacuo. The crude product (0.964 g) was puriﬁed by column

10

11

15

16

17

18

19

20

21

28a

28b

28c

4 (S)

46 (S)

42 (R)

42 (S)

26 (S)

36 (S)

26 (S)

60 (R)

22 (R)

chromatography (U = 17 mm, h = 380 mm, 30 g silica gel, CH₂Cl₂/

43

CH₃OH = 50:1), to give 0.225 g, (30%) of 15 as colorless crystals

and 0.277 g (60%) of the starting N,N-dimethylaminomethyl-

ferrocene.

a

Yields of the isolated compounds after column chromatography.

Enantiomeric excess of the reaction product (1-phenyl-1-propanol) determined

by GC (chiral capillary column Hydrodex-b-TBDAc).

b

Data of 15: Mp 83–85 °C. ½a _D²⁰

= ꢀ90.6 (c 0.60, CHCl₃). Anal.

ꢂ

Calc. for C₃₁H₃₉FeNO (497.49): C, 74.84; H, 7.90; Fe, 11.23; N,

2.82. Found: C, 74.58; H, 7.84; Fe, 11.53; N, 2.93%. MS (EI) m/z

(rel. int.): 497 (M⁺ꢀ, 27), 452 (100), 386 (27), 308 (19), 188 (19).

¹H NMR (600 MHz, CDCl₃, 300 K) d: 7.23–7.19 (m, 2H, arom.),

7.17–7.12 (m, 2H, arom.), 5.27 (br s, 1H, 11-H_b), 4.21 (s, 1H, 4⁰-

H,), 4.14 (s, 6H, 5⁰-H, 5H-Cp), 4.00 (s, 1H, 3⁰-H), 3.86 (d, 1H, 18-

H_b, J = 17.6 Hz), 3.36 (d, 1H, 11-H_a, J = 17.6 Hz), 3.37–3.34 (m, 1H,

6⁰-H_a), 3.16 (d, 1H, 18-H_a, J = 17.6 Hz), 2.44 (br s, 1H, 6-H_endo),

2.35 (d, 1H, 6⁰-H_b, J = 12.5 Hz), 1.91 (s, 6H, N(CH₃)₂), 1.86–1.82

(m, 1H, 5-H_endo), 1.66–1.61 (m, 2H, 4-H, 5-H_exo), 1.40 (s, 3H, 8-

H), 1.37–1.33 (m, 1H, 6-H_exo), 0.94 (s, 3H, 10-H), 0.93 (s, 3H, 9-

H). ¹³C NMR (600 MHz, CDCl₃, 300 K) d: 143.37 (s, 1 arom. C),

142.93 (s, 1 arom. C), 125.96 (d, 1 arom. C), 125.86 (d, 1 arom.

C), 124.19 (d, 1 arom. C), 123.47 (d, 1 arom. C), 95.18 (s, C-1⁰),

87.20 (s, C-2⁰), 81.22 (s, C-2), 71.18 (d, C-5⁰), 71.08 (d, C-3⁰), 70.06

(d, Cp5), 65.68 (d, C-4⁰), 59.78 (s, C-3), 56.76 (d, C-4), 55.68 (s, C-

1), 50.06 (s, C-7), 44.57 (q, 2C, N(CH₃)₂), 44.27 (t, C-18), 42.76 (t,

C-11), 30.46 (t, C-6), 24.42 (q, C-9), 24.05 (t, C-5), 23.93 (q, C-8),

13.50 (q, C-10).

3.17 (d, 1H, 1⁰-H_a, J = 14.4 Hz), 3.01 (d, 1H, 11-H_a, J = 15.7 Hz), 2.87

(d, 1H, 1⁰-H_b, J = 14.4 Hz), 2.76 (d, 1H, 18-H_b, J = 15.3 Hz), 2.23 (s, 6H,

N(CH₃)₂), 1.93–1.88 (m, 1H, 6-H_endo), 1.68–1.62 (m, 3H, 4-H, 5-H),

1.45–1.40 (m, 1H, 6-H_exo), 1.29 (s, 3H, 8-H), 0.81 (s, 3H, 9-H),

0.36 (s, 3H, 10-H). ¹³C NMR (600 MHz, CDCl₃, 300 K) d: 152.14

(s, 1 arom. C), 145.99 (s, 1 arom. C), 143.14 (s, 1 arom. C), 135.93

(s, 1 arom. C), 133.07 (d, 1 arom. C), 127.30 (d, 1 arom. C), 125.77

(d, 1 arom. C), 125.55 (d, 1 arom. C), 124.79 (d, 1 arom. C), 123.55

(d, 1 arom. C), 122.78 (d, 1 arom. C), 120.04 (d, 1 arom. C), 84.30

(s, C-2), 63.28 (s, C-3), 56.28 (d, C-4), 54.57 (s, C-1), 49.13 (s, C-7),

43.82 (q, 2C, N(CH₃)₂), 43.00 (t, C-11), 42.92 (t, C-18), 39.36 (t,

C-1⁰), 31.03 (t, C-6), 24.57 (t, C-5), 23.19 (q, C-8), 23.12 (q, C-9),

11.98 (q, C-10).

4.5. (3R,4R)-4,7,7-trimethyl-3-((6-methylpyridin-2-yl)methyl)-1⁰,3⁰-

dihydrospiro[bicyclo[2.2.1]-heptane-2,2⁰-inden]-3-ol (11)

To

a

stirred solution of 2,6-dimethylpyridine (0.192 g,

1.79 mmol) in 10 ml THF, 2.5 M n-BuLi in hexane (0.72 ml,

1.79 mmol) was added at ꢀ60 °C and the solution was stirred for

1 h. Then 2 (0.350 g 1.40 mmol) was added and the reaction mix-

ture was stirred for 1.5 h at ꢀ60 °C (the reaction progress was mon-

itored by TLC). The reaction was carefully quenched with H₂O and

extracted with Et₂O. The organic extract was dried over anhydrous

Na₂SO₄and the solvent evaporated in vacuo. The crude product was

4.7. (3R,4R)-3-(4-(dimethylamino)pyridin-2-yl)-4,7,7-trimethyl-1⁰,3⁰-

dihydrospiro[bicyclo[2.2.1]-heptane-2,2⁰-inden]-3-ol (16)

To a stirred solution of N,N-dimethylaminoethanol (0.250 g,

2.80 mmol) in 8 ml hexane 2.5 M n-BuLi in hexane (2.24 ml,

5.60 mmol) was added at ꢀ10 °C and the solution was stirred for

0.5 h. Then 4-dimethylaminopyridine (0.173 g, 1.18 mmol) was

added. The mixture was stirred for 1 h at ꢀ5 °C, 2 (0.300 g,

1.18 mmol) was added at ꢀ40 °C and the reaction was stirred for

4 h (the reaction progress was monitored by TLC). The reaction

was carefully quenched with H₂O and extracted with Et₂O. The or-

ganic extract was dried over anhydrous Na₂SO₄and the solvent

evaporated in vacuo. The crude product was puriﬁed by column

puriﬁed by column chromatography (

U = 17 mm, h = 380 mm, 25 g

silica gel, hexane/EtOAc = 250:1), to give 0.375 g, (75%) of 11 as col-

orless crystals. Mp 118–119 °C. ½a _D²⁰

ꢂ

= +60.9 (c 1.02, CHCl₃). Anal.

Calc. for C₂₅H₃₁NO (361.24): C, 83.06; H, 8.64; N, 3.87. Found: C,

83.04; H, 8.65; N, 3.73%. MS (EI) m/z (rel. int.): 361 (M⁺ꢀ, 100), 250

(48), 245 (17), 218(40), 176 (43), 163 (30), 107 (89). ¹H NMR

(600 MHz, CDCl₃, 300 K) d: 7.98 (brs, OH), 7.31 (m, 1H, Ar), 7.05

(d, 1H, Ar, J = 7.3 Hz), 6.91 (m, 2H, Ar), 6.74 (t, 1H, Ar, J = 7.3 Hz),

6.65 (d, 1H, Ar, J = 7.7 Hz), 6.57 (d, 1H, Ar, J = 7.3 Hz), 4.03 (d, 1H,

18-H_a, J = 16.4 Hz), 3.11 (d, 1H, 1⁰-H_a, J = 15.3 Hz), 3.05 (d, 1H, 11-

H_b, J = 16.4 Hz), 3.01 (d, 1H, 1⁰-H_b, J = 15.3 Hz), 2. 92 (d, 1H, 11-H_a,

J = 16.4 Hz), 2.77 (d, 1H, 18_b-H, J = 16.4 Hz), 2.09 (s, 3H, 7⁰-H),

1.69–168 (m, 1H, 4-H), 1.67–1.56 (m, 3H, 5-H, 6-H_exo), 1.39–1.35

(m, 1H, 6-H_endo), 1.40 (s, 3H, 8-H), 0.89 (s, 3H, 9-H), 0.70

(s, 3H, 10-H).¹³C NMR (600 MHz, CDCl₃, 300 K) d: 159.78 (s, 1

arom. C), 155.89 (s, 1 arom. C), 144.56 (s, 1 arom. C), 142.09

(s, 1 arom. C), 136.67 (d, 1 arom. C), 125.36 (d, 1 arom. C), 125.04

(d, 1 arom. C), 123.11 (d, 1 arom. C), 122.66 (d, 1 arom. C), 121.59

(d, 1 arom. C), 120.58 (d, 1 arom. C), 85.30 (s, C-2), 60.88 (s, C-3),

58.58 (d, C-4), 55.19 (s, C-1), 48.78 (s, C-7), 43.46 (t, C-11), 43.15

(t, C-18), 39.92 (t, C-1⁰), 30.36 (t, C-6), 241 (t, C-5), 23.79 (q, C-7⁰),

23.07 (q, C-8), 23.04 (q, C-9), 12.20 (q, C-10).

chromatography

Et₂O:hexane = 3:1), to give 0.090 g, (20%) of 16 as colorless crystals.

Mp 139–140 °C. = ꢀ87.9 (c 0.59, CHCl₃). Anal. Calc. for

₂₅H₃₂N₂O (376.53): C, 79.75; H, 8.57; N, 7.44. Found: C, 79.80;

(U = 17 mm, h = 380 mm, 20 g silica gel,

½ ꢂ

a ²_D⁰

C

H, 8.53; N, 7.50%. MS (EI) m/z (rel. int.): 376 (M⁺ꢀ, 79), 267 (100),

233 (16), 191 (29), 152 (17), 122 (96). ¹H NMR (250 MHz, CDCl₃,

300 K) d: 8.07 (d, 1H, 5⁰-H, J = 6.0 Hz), 7.15 (d, 1H, Ar, J = 6.9 Hz),

7.02 (m, 3H, Ar), 6.57 (d, 1H, 2⁰-H, J = 2.4 Hz), 6.40 (dd, 1H, 4⁰-H,

J = 6.0, 2.4 Hz), 3.77 (d, 1H, 18-H_b), J = 16.5 Hz), 3.19 (dd, 2H,

18-H_a, 11-H_a, J = 16.5, 15.7 Hz), 3.00 (s, 6H, N(CH₃)₂), 2.83 (d, 1H,

11-H_b, J = 15.7 Hz), 2.19–2.08 (m, 1H, 6-H_endo), 1.79–1.63 (m, 3H,

4-H, 5-H), 1.56 (s, 3H, 8-H), 1.46–1.36 (m, 1H, 6-H_exo), 0.96 (s,

3H, 9-H), 0.73 (s, 3H, 10-H). ¹³C NMR (250 MHz, CDCl₃, 300 K) d:

160.64 (s, 1 arom. C), 153.41 (s, 1 arom. C), 145.92 (d, 1 arom. C),

143.86 (s, 1 arom. C), 142.46 (s, 1 arom. C), 125.73 (d, 1 arom. C),

136

G.M. Dobrikov et al. / Polyhedron 45 (2012) 126–143

125.39 (d, 1 arom. C), 123.71 (d, 1 arom. C), 122.97 (d, 1 arom. C),

108.03 (d, 1 arom. C), 105.40 (d, 1 arom. C), 86.91 (s, C-2), 62.05 (s,

C-3), 54.95 (s, C-1), 53.74 (d, C-4), 50.32 (s, C-7), 42.88 (t, C-18),

42.79 (t, C-11), 39.24 (q, 2C, N(CH₃)₂), 30.24 (t, C-6), 24.09 (q, C-

8), 24.01 (s, C-9), 23.37 (t, C-5), 11.59 (q, C-10).

(rel. int.): 395 (M⁺ꢀ, 5), 350 (100), 227 (19), 199 (21), 121 (14).

¹H NMR (250 MHz, CDCl₃, 300 K) d: 5.42 (s, 1H, OH), 4.11–4.16

(m, 2H, 15-H, 16-H_a), 4.09 (s, 5H, 5H-Cp), 4.01 (dd, 1H, 14-H,

J = 2.3, 1.6 Hz), 3.87 (dd, 1H, 13-H, J = 2.3, 1.6 Hz), 2.49 (d, 1H, 16-

H_b, J = 12.2 Hz), 2.17 (s, 6H, N(CH₃)₂), 2.03 (m, 1H, 6-H_endo), 1.71–

1.88 (m, 2H, 7-H_syn, 5-H_endo), 1.62–1.66 (m, 1H, 4-H), 1.58 (s, 3H,

8-H), 1.37 (m, 1H, 5-H_exo), 1.21 (s, 3H, 9-H), 0.95–1.03 (m, 1H, 6-

4.8. (3R,4R)-3-(6-(dimethylamino)pyridin-2-yl)-4,7,7-trimethyl-1⁰,3⁰-

dihydrospiro[bicyclo[2.2.1]-heptane-2,2⁰-inden]-3-ol (17)

H

_exo), 0.85–1.00 (m, 1H, 7-H_anti), 0.34 (s, 3H, 10-H). ¹³C NMR

(250 MHz, CDCl₃, 300 K) d: 96.47 (s, 1C, 2-C), 83.15^⁄(s, 1C, 12-C),

79.81^⁄(s, 1C, 11-C), 70.94 (d, 1C, 14-C), 70.78 (d, 1C, 15-C), 70.02

(d, 5C, Cp5), 66.37 (d, 1C, 13-C), 61.70 (t, 1C, 16-C), 57.37 (s, 1C,

1-C), 49.89 (d, 1C, 4-C), 47.16 (s, 1C, 3-C), 44.87 (q, 2C, N(CH₃)₂),

41.78 (t, 1C, 7-C), 32.15 (t, 1C, 6-C), 28.52 (q, 1C, 8-C), 24.27 (t,

1C, 5-C), 23.34 (q, 1C, 9-C), 18.03 (q, 1C, 10-C).

To a stirred solution of dry N,N-dimethylaminoethanol (0.316 g,

3.54 mmol) in 2 ml hexane 2.5 M n-BuLi in hexane (2.84 ml,

7.08 mmol) was added at ꢀ10 °C and the solution was stirred for

0.5 h. Then 2-dimethylaminopyridine (0.220 g, 1.18 mmol) was

added. The mixture was stirred for 1 h at ꢀ5 °C and ketone 2

(0.300 g, 1.18 mmol) was added at ꢀ40 °C. The reaction mixture

was stirred for 20 h (the reaction progress was monitored by

TLC). The reaction was carefully quenched with H₂O and extracted

with Et₂O. The organic extract was dried over anhydrous Na₂SO₄

and the solvent evaporated in vacuo. The crude product was puri-

Data of 19: Mp 83–85 °C. ½a _D²⁰

= ꢀ25.0 (c 1.00, CHCl₃). Anal. Calc.

ꢂ

for C₂₃H₃₃FeNO (395.19): C, 69.87; H, 8.41; Fe, 14.13; N, 3.54.

Found: C, 69.84; H, 8.40; Fe, 14.14; N, 3.59%. MS (EI) m/z (rel.

int.): 395 (M⁺ꢀ, 10), 350 (100), 227 (28), 199 (27), 121 (18). ¹H

NMR (250 MHz, CDCl₃, 300 K) d: 4.18 (d, 2H, 13-H, 14-H), 4.11 (s,

5H, 5H-Cp), 4.03 (t, 1H, 15-H, J = 2.1 Hz), 3.59 (d, 1H, 16-H_a,

J = 13.8 Hz), 3.11 (d, 1H, 16-H_b, J = 13.8 Hz), 2.30–2.45 (m, 1H, 6-

ﬁed by column chromatography (

U = 17 mm, h = 380 mm, 20 g sil-

ica gel, hexane:Et₂O = 50:1), to give 0.180 g, (40%) of 17 as colorless

crystals. Mp 75–77 °C. ½a _D²⁰

ꢂ

= +89.3 (c 0.27, CHCl₃). Anal. Calc. for

H_endo), 2.29 (s, 6H, N(CH₃)₂), 1.94 (dq, 1H, 7-H_syn, J = 10.2, 2.5 Hz),

C₂₅H₃₂N₂O (376.53): C, 79.75; H, 8.57; N, 7.44. Found: C, 79.83;

H, 8.55; N, 7.49%. MS (EI) m/z (rel. int.): 376 (M⁺ꢀ, 76), 348 (95),

267 (51), 237 (50), 205 (60), 192 (43), 122 (100). ¹H NMR

(250 MHz, CDCl₃, 300 K) d: 7.45 (t, 1H, 3⁰-H, J = 8.0 Hz), 7.15 (d,

1H, 16-H, J = 7.0 Hz), 7.06 (dd, 1H, 15-H, J = 7.2, 7.3 Hz), 7.00 (t,

1H, 14-H, J = 7.2 Hz), 6.97 (d, 1H, 13-H, J = 7.2 Hz), 6.74 (d, 1H, 2⁰-

H, J = 7.6 Hz), 6.60 (s, 1H, OH), 6.37 (d, 1H, 4⁰-H, J = 8.4 Hz), 3.77

(d, 1H, 18-H_b, J = 16.3 Hz), 3.22 (d, 1H, 11-H_a, J = 15.7 Hz), 3.18 (d,

1H, 18-H_a, J = 16.3 Hz), 2.95 (s, 6H, N(CH₃)₂), 2.83 (d, 1H, 11-H_b,

J = 15.7 Hz), 2.05–2.01 (m, 1H, 6-H_endo), 1.80–1.75 (m, 1H, 5-H_endo),

1.73–1.72 (m, 1H, 4-H), 1.70–1.65 (m, 1H, 5-H_exo), 1.57 (s, 3H, 8-H),

1.42–1.37 (m, 1H, 6-H_exo), 0.98 (s, 3H, 9-H), 0.76 (s, 3H, 10-H). ¹³C

NMR (250 MHz, CDCl₃, 300 K) d: 158.54 (s, 1 arom. C), 156.54 (s, 1

arom. C), 143.79 (s, 1 arom. C), 142.62 (s, 1 arom. C), 136.21 (d, 1

arom. C), 125.62 (d, 1 arom. C), 125.34 (d, 1 arom. C), 123.60 (d,

1 arom. C), 112.96 (d, 1 arom. C), 112.62 (d, 1 arom. C), 103.60

(d, 1 arom. C), 87.03 (s, C-2), 62.06 (s, C-3), 54.81 (s, C-1), 53.94

(d, C-4), 50.40 (s, C-7), 43.04 (t, C-18), 42.62 (t, C-11), 37.94 (q,

2C, N(CH₃)₂), 30.11 (t, C-6), 24.01 (q, C-8), 23.97 (q, C-9), 23.34

(t, C-5), 11.61 (q, C-10).

1.72 (m, 1H, 5-H_endo), 1.58 (s, 3H, 10-H), 1.55–1.58 (m, 1H, 4-H),

1.35 (tdd, 1H, 5-H_exo, J = 12.2, 5.3, 4.1 Hz), 1.00–1.14 (m, 1H, 7-H_anti),

1.00–1.13 (m, 1H, 6-H_exo), 1.00 (s, 3H, 9-H), 0.41 (s, 3H, 8-H). ¹³C

NMR (250 MHz, CDCl₃, 300 K) d: 95.25 (s, 1C, C-2), 81.91^⁄(s, 1C,

11-C), 81.87^⁄(s, 1C, 12-C), 71.06 (d, 1C, 15-C), 69.87 (d, 5C, Cp5),

69.52^⁄(d, 1C, 13-C), 65.53^⁄(d, 1C, 14-C), 60.15 (t, 1C, 16-C), 53.49

(s, 1C, 1-C), 50.37 (d, 1C, 4-C), 45.87 (q, 2C, N(CH₃)₂), 45.87 (s, 1C,

3-C), 41.35 (t, 1C, 7-C), 32.17 (t, 1C, 6-C), 28.68 (q, 1C, 8-C), 25.25

(t, 1C, 5-C), 22.39 (q, 1C, 9-C), 20.49 (q, 1C, 10-C).

4.10. (1R,2R)-2-(4-(dimethylamino)pyridin-2-yl)-1,3,3-

trimethylbicyclo[2.2.1]heptan-2-ol (20)

To a solution of 1.79 ml (17.80 mmol) N,N-dimethylaminoetha-

nol in 20 ml hexane was added dropwise at ꢀ5 °C 12.61 ml

(31.50 mmol) 2.5 M solution of n-BuLi in hexane. After stirring

for 30 min at 0 °C was added 0.96 g (7.88 mmol) 4-dimethylamino-

pyridine, and the resulting mixture was stirred for an additional

1 h. The mixture was cooled to ꢀ40 °C and 1.00 g (6.57 mmol)

(ꢀ)-fenchone (3) was added. The reaction was monitored by TLC

(hexane:Et₂O:Et₃N = 30:30:1). The resulting orange mixture was

stirred and allowed to warm to ꢀ20 °C for 2.5 h. The reaction

was quenched with saturated aqueous NH₄Cl and extracted with

Et₂O. The organic phase was washed with water, dried over anhy-

drous Na₂SO₄and the solvent was evaporated in vacuo. The crude

4.9. (1R,2R,pR)-2-(2-((dimethylamino)methyl)ferrocenyl)-1,3,3-

trimethylbicyclo[2.2.1]heptan-2-ol (18) and (1R,2R,pS)-2-(2-

((dimethylamino)methyl)ferrocenyl)-1,3,3-

trimethylbicyclo[2.2.1]heptan-2-ol (19)

product was puriﬁed by column chromatography (

U = 30 mm,

To 0.60 g (2.47 mmol) N,N-dimethylaminomethylferrocene

were added at room temperature 2.50 ml (3.00 mmol) 1.2 M solu-

tion of n-BuLi in hexane. After stirring for 24 h at room tempera-

ture the resulting solution was cooled to 0 °C and 0.45 ml

(2.85 mmol) (ꢀ)-fenchone (3) was added dropwise. The reaction

was monitored by TLC (hexane:Et₂O:Et₃N = 80:40:1). After stirring

for 18 h at room temperature, the reaction was quenched with 5%

aqueous H₃PO₄(pH 4) and the resulting mixture was washed with

Et₂O. The aqueous phase was treated immediately with excess of

solid K₂CO₃(pH 10) and extracted with Et₂O. The organic phase

was washed with water, dried over anhydrous Na₂SO₄and the sol-

vent evaporated in vacuo. The crude product was puriﬁed by col-

h = 320 mm, 70 g silica gel, (a) hexane:Et₂O = 2:1, (b) Et₂O to give

0.39 g (22%) of 20 as white crystals. Mp 140–141 °C. ½a _D²⁰

ꢂ

= +15.1

(c 0.36, CHCl₃). Anal. Calc. for C₁₇H₂₆N₂O (274.40): C, 74.41; H,

9.55; N, 10.21. Found: C, 74.46; H, 9.59; N, 10.18%. MS (EI) m/z

(rel. int.): 274 (M⁺ꢀ, 33), 246 (43), 205 (92), 193 (97), 191 (41),

177 (49), 163 (22), 136 (32), 122 (100). ¹H NMR (600 MHz, CDCl₃,

300 K) d: 8.10 (d, 1H, 5⁸-H, J = 5.9 Hz), 6.70 (d, 1H, 2⁸-H, J = 2.4 Hz),

6.39 (dd, 1H, 4⁸-H, J = 5.9, 2.4 Hz), 6.10 (br s, 1H, OH), 3.02 (s, 6H, 6⁸-

H), 2.35 (m, 1H, 6-H_endo), 2.22 (br d, 1H, 7-H_syn, J = 10.3 Hz), 1.85

(m, 1H, 5-H_endo), 1.77 (m, 1H, 4-H), 1.47 (dddd, 1H, 5-H_exo

,

J = 12.4, 12.4, 4.6, 4.6 Hz), 1.34 (dd, 1H, 7-H_anti, J = 10.3, 1.5 Hz),

1.12 (dt, 1H, 6-H_exo, J = 12.5, 4.6 Hz), 1.05 (s, 3H, 10-H), 0.99 (s,

3H, 9-H), 0.52 (s, 3H, 8-H). ¹³C NMR (600 MHz, CDCl₃, 300 K) d:

153.75 (s, 1C, 1⁸-C), 146.48 (d, 1C, 5⁸-C), 105.83 (d, 1C, 2⁸-C),

105.10 (s, 1C, 3⁸-C), 105.10 (d, 1C, 4⁸-C), 83.44 (s, 1C, 2-C), 51.63

(s, 1C, 1-C), 48.92 (d, 1C, 4-C), 45.67 (s, 1C, 3-C), 42.20 (t, 1C, 7-

C), 39.30 (q, 2C, 6⁸-C), 32.74 (t, 1C, 6-C), 29.35 (q, 1C, 8-C), 24.45

(t, 1C, 5-C), 22.33 (q, 1C, 9-C), 17.56 (q, 1C, 10-C).

umn chromatography (U = 23 mm, h = 580 mm, 100 g silica gel,

hexane:Et₂O:E₃N = 300:100:1) to give 0.23 g (26%) 18 as an orange

solid and 0.46 g (52%) 19 as an orange solid. Overall yield 78%.

Data of 18: Mp 122–124 °C. ½a _D²⁰

= ꢀ43.9 (c 1.02, CHCl₃). Anal.

ꢂ

Calc. for C₂₃H₃₃FeNO (395.19): C, 69.87; H, 8.41; Fe, 14.13; N,

3.54. Found: C, 69.92; H, 8.47; Fe, 14.17; N, 3.60%. MS (EI) m/z

G.M. Dobrikov et al. / Polyhedron 45 (2012) 126–143

137

4.11. (1R,2R)-2-(6-(dimethylamino)pyridin-2-yl)-1,3,3-

4.13. (1R,2R)-2-(1-isopropyl-1H-imidazol-2-yl)-1,3,3-

trimethylbicyclo[2.2.1]heptan-2-ol (21)

trimethylbicyclo[2.2.1]heptan-2-ol (28b)

To a solution of 1.60 ml (15.76 mmol) dry N,N-dimethylamino-

ethanol in 10 ml hexane was added dropwise at ꢀ5 °C 12.60 ml

(31.52 mmol) 2.5 M solution of n-BuLi in hexane. After stirring

for 30 min at 0 °C 0.96 g (7.88 mmol) 2-dimethylaminopyridine

was added, and the resulting mixture was stirred at 0 °C for

1.5 h. The formed dark red solution was cooled to ꢀ30 °C and

1.00 g (6.57 mmol) (ꢀ)-fenchone (3) was added. The reaction was

monitored by TLC (hexane:Et₂O = 20:1) and stirred for 4 h at

ꢀ30 °C. The reaction mixture was quenched with saturated aque-

ous NH₄Cl and extracted with Et₂O. The organic phase was washed

with water, dried over anhydrous Na₂SO₄and the solvent was

evaporated in vacuo. The crude product was puriﬁed by column

To a solution of 0.87 g (7.88 mmol) N-isopropylimidazole in

15 ml hexane and 15 ml THF was added at ꢀ80 °C 3.45 ml

(8.70 mmol) 2.5 M solution of n-BuLi in hexane, and the resulting

mixture was stirred for 2 h at ꢀ65 °C. To the formed yellow solu-

tion was added 1.00 g (6.57 mmol) (ꢀ)-fenchone (3) and the mix-

ture was stirred at ꢀ50 °C. The reaction was monitored by TLC

(hexane:Et₂O = 1:1) and after 2 h was quenched with water and

extracted with Et₂O. The organic phase was washed with water,

dried over anhydrous Na₂SO₄and the solvent was evaporated in

vacuo. The crude product was puriﬁed by column chromatography

(

U = 30 mm, h = 320 mm, 80 g silica gel, hexane:Et₂O = 2:1) to give

1.49 g (86%) 28b as white crystals. Mp 102–103 °C. ½a _D²⁰

= ꢀ58.3 (c

ꢂ

chromatography (

U

= 30 mm, h = 320 mm, 80 g silica gel, (a) hex-

0.74, CHCl₃). Anal. Calc. for C₁₆H₂₆N₂O (262.39): C, 73.24; H, 9.99;

N, 10.68. Found: C, 73.21; H, 9.95; N, 10.69%. MS (EI) m/z (rel.

int.): 262 (M⁺ꢀ, 51), 247 (33), 219 (84), 205 (26), 191 (21), 181

(100), 165 (29), 149 (44), 139 (42), 95 (37). ¹H NMR (250 MHz,

CDCl₃, 300 K) d: 6.93 (d, 1H, 3⁸-H, J = 1.3 Hz), 6.87 (d, 1H, 2⁸-H,

ane:CH₂Cl₂= 40:1, (b) hexane:Et₂O = 40:1) to give 0.43 g (24%) of

21 as a white solid. Mp 49–50 °C. ½a _D²⁰

= ꢀ85.9 (c 0.77, CHCl₃). Anal.

ꢂ

Calc. for C₁₇H₂₆N₂O (274.40): C, 74.41; H, 9.55; N, 10.21%. Found: C,

74.40; H, 9.52; N, 10.24%. MS (EI) m/z (rel. int.): 274 (M⁺ꢀ, 9), 246

(29), 205 (21), 193 (25), 177 (100), 164 (20), 150 (14), 136 (30).

¹H NMR (600 MHz, CDCl₃, 300 K) d: 7.42 (m, 1H, 3⁸-H), 6.74 (d,

1H, 2⁸-H, J = 7.5 Hz), 6.34 (d, 1H, 4⁸-H, J = 8.2 Hz), 6.12 (br s, 1H,

OH), 3.06 (br s, 6H, 6⁸-H), 2.25–2.34 (m, 1H, 6-H_endo), 2.15–2.25

(m, 1H, 7-H_syn), 1.84 (m, 1H, 5-H_endo), 1.76 (m, 1H, 4-H), 1.46

J = 1.3 Hz), 5.15 (septet, 1H, 4⁸-H, J = 6.6 Hz), 2.80 (dq, 1H, 7-H_syn

,

J = 10.4, 4.3, 2.4 Hz), 1.91 (m, 1H, 6-H_endo), 1.81 (s, 1H, OH), 1.72

(m, 1H, 4-H), 1.69 (m, 1H, 5-H_endo), 1.43 (m, 1H, 5-H_exo), 1.42 (d,

3H, 6⁸-H, J = 6.6 Hz), 1.36 (d, 3H, 5⁸-H, J = 6.6 Hz), 1.34 (s, 3H, 8-

H), 1.27 (dd, 1H, 7-H_anti, J = 10.4, 1.5 Hz), 1.19 (dt, 1H, 6-H_exo

,

(dddd, 1H, 5-H_exo, J = 12.5, 12.5, 4.6, 4.6 Hz), 1.29 (dd, 1H, 7-H_anti

,

J = 13.1, 4.0 Hz), 1.08 (s, 3H, 9-H), 0.52 (s, 3H, 10-H). ¹³C NMR

(250 MHz, CDCl₃, 300 K) d: 148.97 (s, 1C, 1⁸-C), 125.90 (d, 1C, 3⁸-

C), 115.09 (d, 1C, 2⁸-C), 84.17 (s, 1C, 2-C), 54.56 (s, 1C, 1-C), 49.64

(d, 1C, 4-C), 48.29 (d, 1C, 4⁸-C), 45.62 (s, 1C, 3-C), 40.67 (t, 1C, 7-

C), 31.23 (t, 1C, 6-C), 27.90 (q, 1C, 8-C), 25.57 (q, 1C, 5⁸-C), 24.94

(t, 1C, 5-C), 23.60 (q, 1C, 6⁸-C), 22.34 (q, 1C, 9-C), 17.66 (q, 1C,

10-C).

J = 10.4, 1.0 Hz), 1.13 (dt, 1H, 6-H_exo, J = 12.5, 4.6 Hz), 1.03 (s, 3H,

10-H), 0.98 (s, 3H, 9-H), 0.51 (s, 3H, 8-H)._⁄¹³C NMR (600 MHz,

CDCl₃, 300 K) d: 156.80^⁄(s, 1C, 1⁸-C), 156.80 (s, 1C, 5⁸-C), 136.58

(d, 1C, 3⁸-C), 110.84 (d, 1C, 2⁸-C), 103.03 (d, 1C, 4⁸-C), 83.49 (s, 1C,

2-C), 51.56 (s, 1C, 1-C), 48.87 (d, 1C, 4-C), 45.71 (s, 1C, 3-C),

41.84 (t, 1C, 7-C), 38.01 (q, 1C, 6⁸-C), 32.63 (t, 1C, 6-C), 29.00 (q,

1C, 8-C), 24.46 (t, 1C, 5-C), 22.42 (q, 1C, 9-C), 17.28 (q, 1C, 10-C).

4.12. (1R,2R)-2-(1-ethyl-1H-imidazol-2-yl)-1,3,3-

trimethylbicyclo[2.2.1]heptan-2-ol (28a)

4.14. (1R,2R)-1,3,3-trimethyl-2-(1-phenyl-1H-imidazol-2-

yl)bicyclo[2.2.1]heptan-2-ol (28c)

To a solution of 0.76 g (7.88 mmol) N-ethylimidazole in 15 ml

hexane and 15 ml THF was added at ꢀ80 °C 3.45 ml (8.70 mmol)

2.5 M solution of n-BuLi in hexane, and the resulting mixture

was stirred for 2 h at ꢀ65 °C. To the formed yellow solution was

added 1.00 g (6.57 mmol) (ꢀ)-fenchone (3) and the mixture was

stirred at ꢀ50 °C. The reaction was monitored by TLC (hex-

ane:Et₂O = 1:1) and after 1.5 h was quenched with water and ex-

tracted with Et₂O. The organic phase was washed with water,

dried over anhydrous Na₂SO₄and the solvent was evaporated in

vacuo. The crude product was puriﬁed by column chromatography

To a solution of 1.04 g (7.21 mmol) N-phenylimidazole in 20 ml

THF was added at ꢀ70 °C 2.90 ml (7.21 mmol) 2.5 M solution of n-

BuLi in hexane, and the resulting mixture was stirred for 1 h at

ꢀ70 °C. To the formed yellow solution was added 1.00 g

(6.57 mmol) (ꢀ)-fenchone (3) and the mixture was stirred at

ꢀ70 °C. The reaction was monitored by TLC (hexane:Et₂O = 2:1)

and after 2 h was quenched with water and extracted with Et₂O.

The organic phase was washed with water, dried over anhydrous

Na₂SO₄and the solvent evaporated in vacuo. The crude product

(

U

= 24 mm, h = 520 mm, 70 g silica gel, hexane:Et₂O = 1:1) to give

was puriﬁed by column chromatography

(U = 30 mm,

1.58 g (97%) 28a as white crystals. Mp 133–134 °C. ½a _D²⁰

ꢂ

= ꢀ56.0 (c

h = 320 mm, 80 g silica gel, hexane:Et₂O = 10:1) to give 1.34 g

0.88, CHCl₃). Anal. Calc. for C₁₅H₂₄N₂O (248.36): C, 72.54; H, 9.74;

N, 11.28. Found: C, 72.45; H, 9.70; N, 11.29%. MS (EI) m/z (rel.

int.): 248 (M⁺ꢀ, 59), 233 (51), 219 (33), 205 (25), 191 (28), 177

(27), 167 (100), 151 (31), 137 (17), 123 (30), 110 (19). ¹H NMR

(250 MHz, CDCl₃, 300 K) d: 6.91 (d, 1H, 3⁸-H, J = 1.2 Hz), 6.78 (d,

1H, 2⁸-H, J = 1.2 Hz), 4.42 (dq, 1H, 4⁸-H_a, J = 14.4, 7.1 Hz), 3.95 (dq,

1H, 4⁸-H_b, J = 14.4, 7.1 Hz), 2.81 (dq, 1H, 7-H_syn, J = 10.3, 4.4,

2.5 Hz), 1.86 (s, 1H, OH), 1.84–1.97 (m, 1H, 6-H_endo), 1.63–1.75

(m, 1H, 5-H_endo), 1.68–1.74 (m, 1H, 4-H), 1.38 (t, 3H, 5⁸-H,

J = 7.1 Hz), 1.36–1.50 (m, 1H, 5-H_exo), 1.33 (s, 3H, 10-H), 1.27 (dd,

1H, 7-H_anti, J = 10.3, 1.5 Hz), 1.18 (dt, 1H, 6-H_exo, J = 12.7, 3.7 Hz),

1.08 (s, 3H, 9-H), 0.49 (s, 3H, 8-H). ¹³C NMR (250 MHz, CDCl₃,

300 K) d: 149.52 (s, 1C, 1⁸-C), 125.76 (d, 1C, 3⁸-C), 118.75 (d, 1C,

2⁸-C), 84.01 (s, 1C, 2-C), 54.27 (s, 1C, 1-C), 49.52 (d, 1C, 4-C),

45.74 (s, 1C, 3-C), 42.64 (t, 1C, 4⁸-C), 40.62 (t, 1C, 7-C), 30.93 (t,

1C, 6-C), 27.49 (q, 1C, 8-C), 25.15 (t, 1C, 5-C), 22.60 (q, 1C, 9-C),

17.58 (q, 1C, 10-C), 17.10 (q, 1C, 5⁸-C).

(69%) 28c as white crystals. Mp 83–84 °C. ½a _D²⁰

= ꢀ36.7 (c 0.75,

ꢂ

CHCl₃). Anal. Calc. for C₁₉H₂₄N₂O (296.41): C, 76.99; H, 8.16; N,

9.45. Found: C, 77.02; H, 8.18; N, 9.47%. MS (EI) m/z (rel. int.):

296 (M⁺ꢀ, 91), 281 (50), 215 (100), 199 (25), 171 (27), 145 (48).

¹H NMR (600 MHz, CDCl₃, 300 K) d: 7.38–7.44 (m, 3H, 7⁸-H, 6⁸-H),

7.26–7.35 (m, 2H, 5⁸-H), 7.06 (d, 1H, 3⁸-H, J = 1.3 Hz), 6.78 (d, 1H,

2⁸-H, J = 1.3 Hz), 2.98 (dq, 1H, 7-H_syn, J = 10.2, 4.0, 2.1 Hz), 1.77–

1.90 (m, 1H, 6-H_endo), 1.72–1.76 (m, 1H, 4-H), 1.51–1.64 (m, 1H,

5-H_endo), 1.40 (dddd, 1H, 5-H_exo, J = 12.5, 12.5, 4.2, 4.2 Hz), 1.28

(dd, 1H, 7-H_anti, J = 10.2, 1.5 Hz), 1.23 (s, 1H, OH), 1.20 (s, 3H, 10-

H), 1.09 (dt, 1H, 6-H_exo, J = 12.5, 4.2 Hz), 0.78 (s, 3H, 9-H), 0.77 (s,

13

3H, 8-H). C NMR (600 MHz, CDCl₃, 300 K) d: 150.63 (s, 1C, 1⁸-

C), 141.12 (s, 1C, 4⁸-C), 128.47 (d, 2C, 6⁸-C), 128.23 (d, 1C, 7⁸-C),

127.05 (d, 2C, 5⁸-C), 126.03 (d, 1C, 3⁸-C), 122.22 (d, 1C, 2⁸-C),

85.15 (s, 1C, 2-C), 54.63 (s, 1C, 1-C), 48.95 (d, 1C, 4-C), 46.30 (s,

1C, 3-C), 40.89 (t, 1C, 7-C), 30.46 (t, 1C, 6-C), 28.45 (q, 1C, 8-C),

24.83 (t, 1C, 5-C), 21.22 (q, 1C, 9-C), 17.50 (q, 1C, 10-C).

138

G.M. Dobrikov et al. / Polyhedron 45 (2012) 126–143

4.15. (1R,2R)-2-(1-benzyl-1H-imidazol-2-yl)-1,3,3-

4.17. (1R,2R)-1,3,3-trimethyl-2-(1-phenyl-1H-benzo[d]imidazol-2-

trimethylbicyclo[2.2.1]heptan-2-ol (28d)

yl)bicyclo[2.2.1]heptan-2-ol (29b)

To a solution of 1.25 g (7.87 mmol) N-benzylimidazole in 20 ml

THF was added at ꢀ70 °C 3.15 ml (7.87 mmol) 2.5 M solution of n-

BuLi in hexane, and the resulting mixture was stirred for 1 h at

ꢀ70 °C (with the formation of an orange-red solution). To this solu-

tion was added 1.00 g (6.57 mmol) (ꢀ)-fenchone (3) and the mix-

ture was stirred at ꢀ70 °C. The reaction was monitored by TLC

(hexane:Et₂O = 2:1) and after 2 h was quenched with water and

extracted with Et₂O. The organic phase was washed with water,

dried over anhydrous Na₂SO₄and the solvent was evaporated in

vacuo. The crude product was puriﬁed by column chromatography

To a solution of 0.95 g (4.89 mmol) N-phenylbenzimidazole in

20 ml THF was added at ꢀ70 °C 1.95 ml (4.89 mmol) 2.5 M solution

of n-BuLi in hexane, and the resulting mixture was stirred for 1.5 h

at ꢀ70 °C. To the formed yellow solution was added 0.67 g

(4.37 mmol) (ꢀ)-fenchone (3) and the mixture was stirred at

ꢀ70 °C. The reaction was monitored by TLC (hexane:Et₂O = 10:1)

and after 3 h was quenched with water and extracted with Et₂O.

The organic phase was washed with water, dried over anhydrous

Na₂SO₄and the solvent evaporated in vacuo. The crude product

was puriﬁed by column chromatography

(U = 30 mm,

(U

= 30 mm, h = 320 mm, 80 g silica gel, (a) hexane, (b) hex-

h = 320 mm, 80 g silica gel, (a) hexane, (b) hexane:Et₂O = 10:1) to

ane:Et₂O = 5:1) to give 1.56 g (76%) 28d as white crystals. Mp

give 0.66 g (39%) 29b as white crystals. Mp 129–130 °C.

74–75 °C. ½a ²_D⁰

ꢂ

= ꢀ70.5 (c 0.67, CHCl₃). Anal. Calc. for C₂₀H₂₆N₂O

½

a ²_D⁰

ꢂ

= ꢀ29.8 (c 0.80, CHCl₃). Anal. Calc. for C₂₃H₂₆N₂O (346.47): C,

(310.43): C, 77.38; H, 8.44; N, 9.02. Found: C, 77.34; H, 8.45; N,

79.73; H, 7.56; N, 8.09. Found: C, 79.75; H, 7.57; N, 8.11%. MS

9.04%. MS (EI) m/z (rel. int.): 310 (M⁺ꢀ, 34), 229 (59), 219 (100),

(EI) m/z (rel. int.): 346 (M⁺ꢀ, 53), 331 (30), 265 (100), 249 (24),

1

91 (86). H NMR (600 MHz, CDCl₃, 300 K) d: 7.23–7.37 (m, 3H, 6⁸-

195 (47). H NMR (600 MHz, CDCl₃, 300 K) d: 7.80 (d, 1H, 3⁸-H,

H, 8⁸-H), 7.07–7.11 (m, 2H, 7⁸-H), 7.00 (d, 1H, 3⁸-H, J = 1.2 Hz),

6.72 (d, 1H, 2⁸-H, J = 1.2 Hz), 5.73 (d, 1H, 4⁸-H_a, J = 15.4 Hz), 5.05

(d, 1H, 4⁸-H_b, J = 15.4 Hz), 2.89 (dq, 1H, 7-H_syn, J = 10.3, 4.0,

2.2 Hz), 1.79–1.93 (m, 1H, 6-H_endo), 1.70–1.78 (m, 1H, 4-H), 1.62–

1.70 m, 1H, 5-H_endo), 1.37–1.51 (m, 1H, 5-H_exo), 1.27–1.33 (m, 1H,

7-H_anti), 1.29 (s, 3H, 10-H), 1.15 (dt, 1H, 6-H_exo, J = 12.7, 3.6 Hz),

1.06 (s, 3H, 9-H), 0.59 (s, 3H, 8-H). ¹³C NMR (600 MHz, CDCl₃,

300 K) d: 149.86 (s, 1C, 1⁸-C), 138.84 (s, 1C, 5⁸-C), 128.75 (d, 2C,

6⁸-C), 127.40 (d, 1C, 8⁸-C), 126.41 (d, 2C, 7⁸-C), 126.03 (d, 1C, 3⁸-

C), 120.53 (d, 1C, 2⁸-C), 84.31 (s, 1C, 2-C), 54.33 (s, 1C, 1-C), 51.70

(t, 1C, 4⁸-C), 49.35 (d, 1C, 4-C), 46.11 (s, 1C, 3-C), 40.77 (t, 1C, 7-

C), 30.80 (t, 1C, 6-C), 27.80 (q, 1C, 8-C), 25.09 (t, 1C, 5-C), 22.55

(q, 1C, 9-C), 17.45 (q, 1C, 10-C).

J = 8.1 Hz), 7.47–7.54 (m, 3H, 10⁸-H, 11⁸-H), 7.35–7.39 (m, 1H, 9⁸-

H_a), 7.28–7.31 (m, 1H, 9⁸-H_b), 7.25 (m, 1H, 4⁸-H), 7.14 (m, 1H, 5⁸-

H), 6.77 (d, 1H, 6⁸-H, J = 8.1 Hz), 3.20 (dq, 1H, 7-H_syn, J = 10.3, 4.1,

2.2 Hz), 1.88 (m, 1H, 6-H_endo), 1.80 (m, 1H, 4-H), 1.61 (m, 1H, 5-H_en-

_do), 1.44 (m, 1H, 5-H_exo), 1.40 (s, 1H, OH), 1.36 (dd, 1H, 7-H_anti

,

J = 10.3, 1.5 Hz), 1.27 (s, 3H, 10-H), 1.15 (dt, 1H, 6-H_exo, J = 13.1,

4.1 Hz), 0.83 (s, 3H, 9-H), 0.82 (s, 3H, 8-H). ¹³C NMR (600 MHz,

CDCl₃, 300 K) d: 156.35 (s, 1C, 1⁸-C), 141.53 (s, 1C, 2⁸-C), 139.36^⁄

(s, 1C, 8⁸-C), 137.54^⁄(s, 1C, 7⁸-C), 129.36^⁄(d, 1C, 9⁸-C_b), 129.00^⁄

(d, 1C, 10⁸-C_a), 128.91^⁄(d, 1C, 10⁸-C_b), 127.15 (d, 1C, 9⁸-C_a),

128.57 (d, 1C, 11⁸-C), 122.32 (d, 1C, 5⁸-C), 121.95 (d, 1C, 4⁸-C),

119.34 (d, 1C, 3⁸-C), 110.28 (d, 1C, 6⁸-C), 85.58 (s, 1C, 2-C), 55.06

(s, 1C, 1-C), 49.04 (d, 1C, 4-C), 46.11 (s, 1C, 3-C), 41.05 (t, 1C, 7-

C), 30.60 (t, 1C, 6-C), 28.64 (q, 1C, 8-C), 24.87 (t, 1C, 5-C), 21.23

(q, 1C, 9-C), 17.53 (q, 1C, 10-C).

4.16. (1R,2R)-2-(1-isopropyl-1H-benzo[d]imidazol-2-yl)-1,3,3-

trimethylbicyclo[2.2.1] heptan-2-ol (29a)

4.18. (1R,2R)-2-(1-benzyl-1H-benzo[d]imidazol-2-yl)-1,3,3-

To a solution of 1.16 g (7.23 mmol) N-isopropylbenzimidazole

in 15 ml hexane and 15 ml THF was added at ꢀ80 °C 2.90 ml

(7.23 mmol) 2.5 M solution of n-BuLi in hexane, and the resulting

mixture was stirred for 2 h at ꢀ65 °C. To the formed yellow solu-

tion was added 1.00 g (6.57 mmol) (ꢀ)-fenchone (3) and the mix-

ture was stirred at ꢀ40 °C. The reaction was monitored by TLC

(Et₂O) and after 3.5 h was quenched with water and extracted with

Et₂O. The organic phase was washed with water, dried over anhy-

drous Na₂SO₄and the solvent was evaporated in vacuo. The crude

trimethylbicyclo[2.2.1]heptan-2-ol (29c)

To a solution of 0.91 g (4.37 mmol) N-benzylbenzimidazole in

20 ml THF was added at ꢀ70 °C 1.75 ml (4.37 mmol) 2.5 M solution

of n-BuLi in hexane, and the resulting mixture was stirred for 1 h at

ꢀ70 °C. To the formed yellow solution was added 0.67 g

(4.37 mmol) (ꢀ)-fenchone (3) and the mixture was stirred at

ꢀ70 °C. The reaction was monitored by TLC (hexane:Et₂O = 5:1)

and after 3.5 h was quenched with water and extracted with

Et₂O. The organic phase was washed with water, dried over anhy-

drous Na₂SO₄and the solvent evaporated in vacuo. The crude prod-

product was puriﬁed by column chromatography (

U = 20 mm,

h = 280 mm, 34 g silica gel, (a) hexane:Et₂O = 50:1, (b) hex-

ane:Et₂O = 2:1) to give 0.54 g (26%) 29a as white crystals. Mp

uct was puriﬁed by column chromatography

h = 320 mm, 80 g silica gel, hexane:CH₂Cl₂= 2:1). The obtained

product was puriﬁed again by column chromatography

(U = 30 mm,

135–136 °C.

½

a ²_D⁰

ꢂ

= ꢀ41.1 (c 0.83, CHCl₃). Anal. Calc. for

C₂₀H₂₈N₂O (312.45): C, 76.88; H, 9.03; N, 8.97. Found: C, 76.82;

H, 9.00; N, 8.99%. MS (EI) m/z (rel. int.): 312 (M⁺ꢀ, 54), 269 (98),

231 (100), 215 (33), 189 (53), 118 (43). ¹H NMR (250 MHz, CDCl₃,

300 K) d: 7.76 (m, 1H, 6⁸-H), 7.56 (m, 1H, 3⁸-H), 7.15–7.23 (m, 2H,

(

U = 20 mm, h = 280 mm, 40 g silica gel, hexane:Et₂O = 5:1) to give

1.02 g (65%) 29c as white crystals. Mp 135–136 °C. ½a _D²⁰

= ꢀ6.4 (c

ꢂ

0.43, CHCl₃). Anal. Calc. for C₂₄H₂₈N₂O (360.49): C, 79.96; H, 7.83;

N, 7.77. Found: C, 79.99; H, 7.80; N, 7.75%. MS (EI) m/z (rel. int.):

360 (M⁺ꢀ, 54), 279 (94), 269 (100), 207 (25), 119 (24), 91 (97). ¹H

NMR (600 MHz, CDCl₃, 300 K) d: 7.79 (m, 1H, 3⁸-H), 7.17–7.32

(m, 4H, 10⁸-H, 2 arom. H), 7.10–7.16 (m, 2H, arom. H), 7.00–7.07

(m, 2H, 11⁸-H), 6.03 (d, 1H, 8⁸-H_a, J = 16.2 Hz), 5.24 (d, 1H, 8⁸-H_b,

J = 16.2 Hz), 3.13 (dq, 1H, 7-H_syn, J = 10.4, 4.0, 2.3 Hz), 1.82–1.94

(m, 1H, 6-H_endo), 1.77–1.83 (m, 1H, 4-H), 1.80 (s, 1H, OH), 1.67–

1.78 (m, 1H, 5-H_endo), 1.40–1.55 (m, 1H, 5-H_exo), 1.37–1.42 (m,

1H, 7-H_anti), 1.37 (s, 3H, 10-H), 1.21 (dt, 1H, 6-H_exo, J = 12.9,

3.8 Hz), 1.12 (s, 3H, 9-H), 0.62 (s, 3H, 8-H). ¹³C NMR (600 MHz,

CDCl₃, 300 K) d: 156.29 (s, 1C, 1⁸-C), 141.91^⁄(s, 1C, 2⁸-C), 138.33^⁄

(s, 1C, 9⁸-C), 135.47^⁄(s, 1C, 7⁸-C), 128.72_⁄(d, 2C, 10⁸-C), 127.11_⁄^⁄(d,

1C, 12⁸-C), 125.61 (d, 2C, 11⁸-C), 122.28 (d, 1C, 6⁸-C), 121.74 (d,

4⁸-H, 5⁸-H), 5.58 (septet, 1H, 8⁸-H, J = 7.0 Hz), 3.01 (dq, 1H, 7-H_syn

,

J = 10.4, 4.3, 2.3 Hz), 1.98 (s, 1H, OH), 1.92–2.04 (m, 1H, 6-H_endo),

1.70–1.80 (m, 2H, 4-H, 5-H_endo), 1.67 (d, 3H, 10⁸-H, J = 7.0 Hz),

1.62 (d, 3H, 9⁸-H, J = 7.0 Hz), 1.43–1.57 (m, 1H, 5-H_exo), 1.41 (s,

3H, 10-H), 1.38 (dd, 7-H_anti, J = 10.4, 1.5 Hz), 1.26 (dt, 1H, 6-H_exo

,

J = 12.7, 3.9 Hz), 1.17 (s, 3H, 9-H), 0.65 (s, 3H, 8-H)_⁄. ¹³C NMR

(250 MHz, CDCl₃, 300 K) d: 155.70 (s, 1C, 1⁸-C), 142.66 (s, 1C, 2⁸-

C), 133.08^⁄(s, 1C, 7⁸-C), 121.30^⁄(d, 1C, 4⁸-C), 120.89^⁄(d, 1C, 5⁸-C),

120.07 (d, 1C, 6⁸-C), 112.63 (d, 1C, 3⁸-C), 84.69 (s, 1C, 2-C), 55.40

(s, 1C, 1-C), 49.89 (d, 1C, 4-C), 48.66 (d, 1C, 8⁸-C), 45.09 (s, 1C, 3-

C), 40.91 (t, 1C, 7-C), 31.62 (t, 1C, 6-C), 28.31 (q, 1C, 8-C), 24.83

(t, 1C, 5-C), 22.17 (q, 1C, 9-C), 21.98 (q, 1C, 9⁸-C), 20.87 (q, 1C,

10⁸-C), 17.80 (q, 1C, 10-C).

G.M. Dobrikov et al. / Polyhedron 45 (2012) 126–143

139

1C, 5⁸-C), 119.70 (d, 1C, 3⁸-C), 109.88^⁄(d, 1C, 4⁸-C), 84.73 (s, 1C, 2-

C), 54.76 (s, 1C, 1-C), 49.47 (t, 1C, 8⁸-C), 49.40 (d, 1C, 4-C), 45.77 (s,

1C, 3-C), 40.91 (t, 1C, 7-C), 30.87 (t, 1C, 6-C), 27.98 (q, 1C, 8-C),

25.14 (t, 1C, 5-C), 22.64 (q, 1C, 9-C), 17.48 (q, 1C, 10-C).

0.53 (s, 3H, 8-H)_⁄. ¹³C NMR (600 MHz, CDCl₃, 300 K) d: 162.88^⁄(s,

1C, 1⁸-C), 145.41 (s, 1C, 9⁸-C), 129.39^⁄(d, 1C, 7⁸-C), 129.38 (d, 1C,

6⁸-C), 128.82 (d, 1C, 8⁸-C), 127.11 (d, 1C, 3⁸-C), 126.82 (s, 1C, 4⁸-

C), 126.33 (d, 1C, 5⁸-C), 121.63^⁄(d, 1C, 2⁸-C), 83.93 (s, 1C, 2-C),

52.13 (s, 1C, 1-C), 48.76 (d, 1C, 4-C), 46.56 (s, 1C, 3-C), 42.31 (t,

1C, 7-C), 32.66 (t, 1C, 6-C), 29.21 (q, 1C, 8-C), 24.26 (t, 1C, 5-C),

22.48 (q, 1C, 9-C), 17.18 (q, 1C, 10-C).

4.19. (1R,2R)-1,3,3-trimethyl-2-(1-methyl-1H-indol-2-

yl)bicyclo[2.2.1]heptan-2-ol (30)

To a solution of 0.52 g (3.96 mmol) N-methylindole in 10 ml

THF was added dropwise at room temperature 2.35 ml

(3.96 mmol) 1.7 M solution of t-BuLi in pentane. After stirring for

1 h, the formed yellow precipitate was cooled to 0 °C and 0.50 g

(3.28 mmol) (ꢀ)-fenchone (3) was added. The reaction was moni-

tored by TLC (hexane:Et₂O = 10:1) and stirred for 30 min. The

formed clear dark yellow mixture was quenched with water and

extracted with Et₂O. The organic phase was washed with water,

dried over anhydrous Na₂SO₄and the solvent was evaporated in

vacuo. The crude product was puriﬁed by column chromatography

4.21. (1R,2R)-1,3,3-trimethyl-2-(thiophen-2-yl)bicyclo[2.2.1]heptan-

2-ol (32) and (1R,1⁰R,2R,2⁰R)-2,2⁰-(thiophen-2,5-

diyl)bis(trimethylbicyclo[2.2.1]heptan-2-ol) (33)

To 0.63 ml (7.88 mmol) thiophene was added at 0 °C 7.23 ml

(8.67 mmol) 1.2 M solution of n-BuLi in hexane. To this solution

was added dropwise 7 ml THF and the mixture was allowed to

warm to room temperature for 15 min. The resulting mixture was

cooled again to 0 °C and 1.06 ml (6.57 mmol) (ꢀ)-fenchone (3)

was added dropwise. The reaction was monitored by TLC (hex-

ane:Et₂O = 10:1) and after stirring for 20 min was quenched with

saturated aqueous NH₄Cl and extracted with Et₂O. The organic

phase was washed with water, dried over anhydrous Na₂SO₄and

the solvent was evaporated in vacuo. The crude product was puri-

(U = 30 mm, h = 320 mm, 80 g silica gel, (a) hexane:Et₂O = 50:1, (b)

hexane:Et₂O = 20:1) to give 0.85 g (91%) of 30 as white crystals. Mp

119–120 °C. ½a ²_D⁰

= ꢀ63.1 (c 0.75, CHCl₃). Anal. Calc. for C₁₉H₂₅NO

ꢂ

(283.41): C, 80.52; H, 8.89; N, 4.94. Found: C, 80.55; H, 8.92; N,

4.91%. MS (EI) m/z (rel. int.): 283 (M⁺ꢀ, 100), 202 (32), 158 (76),

ﬁed by column chromatography (U = 30 mm, h = 335 mm, 80 g sil-

1

131 (22). H NMR (250 MHz, CDCl₃, 300 K) d: 7.54 (ddd, 1H, 4⁸-H,

ica gel, hexane:Et₂O = 50:1) to give 0.12 g (3%) pure 33 as white

crystals and a fraction containing 32 and (ꢀ)-fenchone. After evap-

oration of the solvent the crude 32 was dissolved in 100 ml Et₂O

and treated with 2.65 g (70 mmol) of LiAlH₄for 1 h at room temper-

ature. The mixture was carefully quenched with 40 ml water and

ﬁltered through Celite. The organic layer was separated, washed

with water and dried over anhydrous Na₂SO₄. After evaporation

of solvent, the crude product was puriﬁed by column chromatogra-

J = 7.6, 1.3, 0.7 Hz), 7.28 (ddd, 1H, 7⁸-H, J = 8.2, 2.0, 0.7 Hz), 7.17

(m, 1H, 6⁸-H), 7.07 (m, 1H, 5⁸-H), 6.52 (d, 1H, 2⁸-H, J = 0.8 Hz),

3.94 (s, 3H, 9⁸-H), 2.56 (dq, 1H, 7-H_syn, J = 10.4, 4.5, 2.3 Hz), 2.17

(m, 1H, 6-H_endo), 1.70–1.82 (m, 2H, 4-H, 5-H_endo), 1.72 (s, 1H,

OH), 1.45 (m, 1H, 5-H_exo), 1.36 (m, 1H, 7-H_anti), 1.34 (s, 3H, 8-H),

1.22 (dt, 1H, 6-H_exo, J = 12.6, 3.8 Hz), 1.20 (s, 3H, 9-H), 0.56 (s,

13

3H, 10-H). C NMR (250 MHz, CDCl₃, 300 K) d: 142.28 (s, 1C, 1⁸-

C), 137.21 (s, 1C, 8⁸-C), 126.76 (s, 1C, 3⁸-C), 121.07 (d, 1C, 6⁸-C),

120.12 (d, 1C, 4⁸-C), 119.31 (d, 1C, 5⁸-C), 109.11 (d, 1C, 7⁸-C),

102.20 (d, 1C, 2⁸-C), 83.94 (s, 1C, 2-C), 53.94 (s, 1C, 1-C), 50.47 (d,

1C, 4-C), 44.64 (s, 1C, 3-C), 40.67 (t, 1C, 7-C), 33.20 (q, 1C, 9⁸-C),

32.00 (t, 1C, 6-C), 28.61 (q, 1C, 8-C), 25.14 (t, 1C, 5-C), 22.60 (q,

1C, 9-C), 18.30 (q, 1C, 10-C).

phy (U = 32 mm, h = 580 mm, 150 g silica gel, (a) hexane and (b)

hexane:Et₂O = 50:1) to give 1.19 g (77%) 32 as white crystals.

Data of 32: Mp 49–50 °C. ½a _D²⁰

= ꢀ59.4 (c 1.05, CHCl₃). Anal.

ꢂ

Calc. for C₁₄H₂₀OS (236.37): C, 71.14; H, 8.53; S, 13.57. Found: C,

71.12; H, 8.50; S, 13.59%. MS (EI) m/z (rel. int.): 236 (M⁺ꢀ, 41),

153 (100), 140 (31), 123 (32), 111 (60). ¹H NMR (250 MHz, CDCl₃,

300 K) d: 7.13 (dd, 1H, 4⁸-H, J = 4.9, 1.5 Hz), 6.94–7.00 (m, 2H, 2⁸-H,

3⁸-H), 2.21 (dq, 1H, 7-H_syn, J = 10.5, 4.4, 2.4 Hz), 2.00–2.13 (m, 1H,

6-H_endo), 2.05 (s, 1H, OH), 1.71–1.83 (m, 2H, 4-H, 5-H_endo), 1.48

(m, 1H, 5-H_exo), 1.34 (dd, 1H, 7-H_anti, J = 10.5, 1.7 Hz), 1.21 (dt,

1H, 6-H_exo, J = 12.5, 4.2 Hz), 1.05 (s, 3H, 10-H), 1.04 (s, 3H, 9-H),

0.66 (s, 3H, 8-H). ¹³C NMR (250 MHz, CDCl₃, 300 K) d: 151.07 (s,

1C, 1⁸-C), 126.34^⁄(d, 1C, 3⁸-C), 123.95^⁄(d, 1C, 2⁸-C), 122.38 (d, 1C,

4⁸-C), 85.22 (s, 1C, 2-C), 53.46 (s, 1C, 1-C), 48.89 (d, 1C, 4-C),

45.81 (s, 1C, 3-C), 41.34 (t, 1C, 7-C), 31.51 (t, 1C, 6-C), 29.16 (q,

1C, 8-C), 24.75 (t, 1C, 5-C), 21.28 (q, 1C, 9-C), 17.64 (q, 1C, 10-C).

4.20. (1R,2R)-1,3,3-trimethyl-2-(quinolin-2-yl)bicyclo[2.2.1]heptan-

2-ol (31)

To a solution of 3.6 ml (31.50 mmol) dry N,N-dimethylamino-

ethanol in 10 ml hexane was added dropwise at ꢀ5 °C 25.2 ml

(62.80 mmol) 2.5 M solution of n-BuLi in hexane. After stirring

for 30 min at 0 °C, the mixture was cooled to ꢀ78 °C and 0.93 ml

(7.88 mmol) quinoline was added dropwise. After stirring for

30 min, 5 ml Et₂O and 1.00 g (6.57 mmol) (ꢀ)-fenchone (3) were

added and the mixture was stirred at ꢀ78 °C for additional 1 h.

The reaction was monitored by TLC (hexane:Et₂O = 10:1),

quenched with 10% HCl and warmed to room temperature (pH

4). The resulting mixture was washed with Et₂O and aqueous

phase was treated with solid K₂CO₃(pH 10–11) and extracted with

Et₂O. The organic phase was washed with water, dried over anhy-

drous Na₂SO₄and the solvent was evaporated in vacuo. The crude

Data of 33: Mp 102–104 °C. ½a _D²⁰

= ꢀ71.9 (c 0.99, CHCl₃). Anal.

ꢂ

Calc. for C₂₄H₃₆O₂S (388.61): C, 74.18; H, 9.34; S, 8.25. Found: C,

74.26; H, 9.45; S, 8.31%. MS (EI) m/z (rel. int.): 388 (M⁺ꢀ, 76), 305

(62), 265 (64), 235 (99), 181 (47), 153 (52), 123 (91), 111 (26), 81

1

(100). H NMR (250 MHz, CDCl₃, 300 K) d: 6.79 (s, 2H, 2⁸-H), 2.18

(dq, 2H, 7-H_syn, J = 10.5, 4.2, 2.3 Hz), 2.07 (m, 2H, 6-H_endo), 1.95 (s,

2H, OH), 1.69–1.80 (m, 4H, 4-H, 5-H_endo), 1.45 (m, 2H, 5-H_exo),

1.30 (dd, 2H, 7-H_anti, J = 10.5, 1.5 Hz), 1.17 (dt, 2H, 6-H_exo, J = 12.6,

4.1 Hz), 1.05 (s, 6H, 10-H), 1.01 (s, 6H, 9-H), 0.68 (s, 6H, 8-H). ¹³C

NMR (250 MHz, CDCl₃, 300 K) d: 147.21 (s, 2C, 1⁸-C), 123.31 (d,

2C, 2⁸-C), 85.05 (s, 2C, 2-C), 53.36 (s, 2C, 1-C), 48.90 (d, 2C, 4-C),

45.71 (s, 2C, 3-C), 41.31 (t, 2C, 7-C), 31.41 (t, 2C, 6-C), 29.19 (q,

2C, 8-C), 24.80 (t, 2C, 5-C), 21.40 (q, 2C, 9-C), 17.71 (q, 2C, 10-C).

product was puriﬁed by column chromatography (

U = 33 mm,

h = 400 mm, 110 g silica gel, (a) hexane, (b) hexane:Et₂O = 40:1)

to give 0.31 g (17%) of 31 as white crystals. Mp 125–126 °C.

½

a ²_D⁰

ꢂ

= ꢀ55.8 (c 0.45, CHCl₃). Anal. Calc. for C₁₉H₂₃NO (281.39): C,

81.10; H, 8.24; N, 4.98. Found: C, 81.14; H, 8.22; N, 4.95%. MS

(EI) m/z (rel. int.): 281 (M⁺ꢀ, 4), 200 (83), 184 (100), 170 (28), 129

1

(68). H NMR (600 MHz, CDCl₃, 300 K) d: 8.09 (m, 1H, 6⁸-H), 8.03

(m, 1H, 8⁸-H), 7.81 (m, 1H, 3⁸-H), 7.66–7.73 (2H, 2⁸-H, 7⁸-H), 7.53

(m, 1H, 5⁸-H), 6.42 (br s, 1H, OH), 2.32–2.47 (m, 2H, 6-H_endo, 7-

4.22. (1R,2R)-2-(benzo[d]thiazol-2-yl)-1,3,3-

trimethylbicyclo[2.2.1]heptan-2-ol (34)

H_syn), 1.87–1.98 (m, 1H, 5-H_endo), 1.86 (m, 1H, 4-H), 1.49–1.61

(m, 1H, 5-H_exo), 1.44 (dd, 1H, 7-H_anti, J = 10.5, 1.4 Hz), 1.17 (dt,

1H, 6-H_exo, J = 12.6, 4.7 Hz), 1.03 (s, 3H, 9-H), 0.97 (s, 3H, 10-H),

To a solution of 1.06 g (7.88 mmol) benzothiazole in 10 ml THF

was added dropwise at ꢀ85 °C 3.15 ml (7.88 mmol) 2.5 M solution

140

G.M. Dobrikov et al. / Polyhedron 45 (2012) 126–143

of n-BuLi in hexane. The resulting orange mixture was stirred for

1 h at ꢀ85 °C and (ꢀ)-fenchone (3) was added. The reaction was

monitored by TLC (hexane/Et₂O = 20:1) and after additional stir-

ring for 1 h at ꢀ85 °C the resulting brown mixture was quenched

with water, warmed to room temperature and extracted with

Et₂O. The organic phase was washed with water, dried over anhy-

drous Na₂SO₄and the solvent was evaporated in vacuo. The crude

(19.70 mmol) (ꢀ)-fenchone (3). The reaction was monitored by

TLC (hexane:Et₂O = 2:1) and stirred for 30 min at ꢀ80 °C. The

resulting clear yellow mixture was quenched with saturated aque-

ous NH₄Cl, warmed to room temperature and extracted with Et₂O.

The organic phase was washed with water, dried over anhydrous

Na₂SO₄and the solvent was evaporated in vacuo. The crude prod-

uct was puriﬁed by column chromatography

(U = 30 mm,

product was puriﬁed by column chromatography (

U

= 30 mm,

h = 320 mm, 80 g silica gel, hexane:Et₂O = 2:1) to give 3.78 g

(99%) of 36 as white crystals. The analytical data for 36 are identi-

cally to that presented in the literature [3a].

h = 340 mm, 80 g silica gel, (a) hexane, (b) hexane/Et₂O = 80:1) to

give 1.55 g (82%) 34 as white crystals. Mp 73–74 °C. ½a _D²⁰

= ꢀ39.4

ꢂ

(c 0.83, CHCl₃). Anal. Calc. for C₁₇H₂₁NOS (287.42): C, 71.04; H,

7.36; N, 4.87; S, 11.16. Found: C, 71.08; H, 7.32; N, 4.90; S,

11.18%. MS (EI) m/z (rel. int.): 287 (M⁺ꢀ, 22), 206 (100), 190 (42),

176 (37), 136 (67). ¹H NMR (250 MHz, CDCl₃, 300 K) d: 8.00 (dq,

1H, 6⁸-H, J = 8.0, 1.2, 0.6 Hz), 7.87 (dq, 1H, 3⁸-H, J = 8.0, 1.2,

0.6 Hz), 7.45 (dt, 1H, 5⁸-H, J = 7.1, 1.2 Hz), 7.35 (dt, 1H, 4⁸-H,

J = 7.1, 1.2 Hz), 3.08 (br s, 1H, OH), 2.86 (dd, 1H, 7-H_syn, J = 10.5,

1.2 Hz), 2.00 (m, 1H, 6-H_endo), 1.76–1.88 (m, 1H, 5-H_endo), 1.83–

1.87 (m, 1H, 4-H), 1.54 (dddd, 1H, 5-H_exo, J = 12.7, 12.7, 4.4,

4.25. (3R,4R)-3-(2-aminoethyl)-4,7,7-trimethyl-1⁰,3⁰-

dihydrospiro[bicyclo[2.2.1]heptane-2,2⁰-inden]-3-ol (37)

To a suspension of LiAlH₄(0.34 g, 8.88 mmol) in 30 ml Et₂O was

added dropwise a solution of 35 (0.328 g, 1.11 mmol) in 10 ml Et₂O

at room temperature, and the resulting mixture was stirred for 1 h.

The reaction mixture was carefully quenched with H₂O and ex-

tracted with Et₂O. The organic extract was dried over anhydrous

Na₂SO₄and the solvent evaporated in vacuo. The crude product

4.4 Hz), 1.36 (dd, 1H, 7-H_anti, J = 10.5, 1.6 Hz), 1.25 (dt, 1H, 6-H_exo

,

J = 12.7, 3.9 Hz), 1.09 (s, 3H, 9-H), 1.04 (s, 3H, 10-H), 0.81 (s, 3H,

8-H). ¹³C NMR (250 MHz, CDCl₃, 300 K) d: 177.65 (s, 1C,

1⁸-C), 152.91 (s, 1C, 7⁸-C), 134.77 (s, 1C, 2⁸-C), 125.51 (d, 1C, 4⁸-C),

124.47 (d, 1C, 5⁸-C), 122.91 (d, 1C, 6⁸-C), 121.28 (d, 1C, 3⁸-C),

86.59 (s, 1C, 2-C), 54.02 (s, 1C, 1-C), 48.75 (d, 1C, 4-C), 46.22

(s, 1C, 3-C), 40.91 (t, 1C, 7-C), 30.72 (t, 1C, 6-C), 28.56 (q, 1C, 8-C),

25.25 (t, 1C, 5-C), 21.92 (q, 1C, 9-C), 17.03 (q, 1C, 10-C).

was puriﬁed by column chromatography

(U = 20 mm,

h = 280 mm, 20 g silica gel, Et₂O:CH₃OH:Et₃N = 100:1:1), to give

0.330 g, (99%) of 37 as a waxy solid. ½a _D²⁰

ꢂ

= +57.6 (c 0.60, CHCl₃).

Anal. Calc. for C₂₀H₂₉NO (295.42): C, 80.22; H, 9.76; N, 4.68. Found:

C, 80.29; H, 9.73; N, 4.70%. MS (EI) m/z (rel. int.): 299 (M⁺ꢀ, 64), 252

(24), 188 (100), 171 (24), 159 (61), 156 (60), 142 (87), 128 (47), 115

(56). ¹H NMR (600 MHz, CDCl₃, 300 K) d: 7.09–7.08 (m, 1H, Ar),

7.04–6.99 (m, 3H, Ar), 3.97 (d, 1H, 18-H_a, J = 16.1 Hz), 3.02 and

2.95 (AB-system, 2H, 11-H, J = 16.4 Hz), 2.75–2.71 (m, 1H, 2⁰-H_a),

2.70 (d, 1H, 18-H_b, J = 16.1 Hz), 2.24–2.20 (m, 1H, 2⁰-H_b), 1.70–

1.66 (m, 1H, 1⁰-H_a), 1.62–1.57 (m, 1H, 1⁰-H_b), 1.58 (d, 1H, 4-H,

J = 4.3 Hz), 1.54–1.49 (m, 1H, 5-H_exo), 1.44–1.40 (m, 1H, 5-H_endo),

1.37–1.33 (m, 1H, 6-H_endo), 1.26–1.21 (m, 1H, 6-H_exo), 1.25 (s, 3H,

8-H), 0.83 (s, 3H, 10-H), 0.80 (s, 3H, 9-H). ¹³C NMR (600 MHz,

CDCl₃, 300 K) d: 145.27 (s, 1 arom. C), 142.87 (s, 1 arom. C),

125.94 (d, 1 arom. C), 125.66 (d, 1 arom. C), 123.97 (d, 1 arom.

C), 122.83 (d, 1 arom. C), 85.59 (s, C-2), 60.84 (s, C-3), 58.68 (d,

C-4), 55.08 (s, C-1), 48.71 (s, C-7), 43.25 (t, C-11), 42.89 (t, C-18),

38.68 (t, C-2⁰), 34.27 (t, C-1⁰), 29.89 (t, C-6), 24.20 (t, C-5), 23.10

(q, C-9), 22.96 (q, C-8), 12.25 (q, C-10).

4.23. 2-((3R,4R)-3-hydroxy-4,7,7-trimethyl-1⁰,3⁰-

dihydrospiro[bicyclo[2.2.1]heptane-2,2⁰-indene]-3-yl)acetonitrile (35)

To a stirred solution of acetonitrile (0.174 g, 4.25 mmol) in 4 ml

THF 2.5 M n-BuLi in hexane (1.42 ml, 3.54 mmol) was added at

ꢀ78 °C. After stirring for 45 min at ꢀ78 °C, to the formed white

precipitate was added 2 (0.300 g, 1.18 mmol) and the reaction

was stirred for 3 h at ꢀ78 °C (the reaction progress was monitored

by TLC). The reaction was carefully quenched with saturated aque-

ous NH₄Cl, warmed to room temperature and extracted with Et₂O.

The organic extract was dried over anhydrous Na₂SO₄and the sol-

vent evaporated in vacuo. The crude product was puriﬁed by col-

umn chromatography (

U = 17 mm, h = 380 mm, 20 g silica gel,

hexane:Et₂O = 4:1), to give 0.330 g, (95%) of 35 as colorless crystals.

4.26. (1R,2R,4S)-2-(2-aminoethyl)-1,3,3-

trimethylbicyclo[2.2.1]heptan-2-ol (38)

Mp 93–94 °C. ½a ²_D⁰

ꢂ

= +80.6 (c 0.56, CHCl₃). Anal. Calc. for C₂₀H₂₅NO

(295.42): C, 81.31; H, 8.53; N, 4.74. Found: C, 81.39; H, 8.55; N,

4.78%. MS (EI) m/z (rel. int.): 295 (M⁺ꢀ, 5), 277 (40), 185 (18), 145

(60), 142 (100), 95 (28). ¹H NMR (600 MHz, CDCl₃, 300 K) d:

7.18–7.12 (m, 4H, Ar), 3.75 (d, 1H, 18-H_a, J = 15.8 Hz), 3.02 and

2.96 (AB-system, 2H, 11-H, J = 16.7 Hz), 2.88 (dd, 2H, 1⁰-H_a, 18-

H_b, J = 16.8, 15.8 Hz), 2.40 (d, 1H, 1⁰-H_b, J = 16.8 Hz), 1.89 (s, 1H,

OH), 1.78 (d, 1H, 4-H, J = 4.1 Hz), 1.79–1.66 (m, 1H, 5-H_exo), 1.56–

1.51 (m, 2H, 6-H_exo, 5-H_endo), 1.38–1.32 (m, 1H, 6-H_endo), 1.35 (s,

3H, 8-H), 1.06 (s, 1H, 10-H), 0.92 (s, 3H, 9-H). ¹³C NMR

(600 MHz, CDCl₃, 300 K) d: 143.62 (s, 1 arom. C), 141.06 (s, 1 arom.

C), 126.82 (d, 1 arom. C), 126.60 (d, 1 arom. C), 123.83 (d, 1 arom.

C), 123.24 (d, 1 arom. C), 118.34 (s, CN), 81.87 (s, C-2), 61.19 (s, C-

3), 56.26 (d, C-4), 54.98 (s, C-1), 49.03 (s, C-7), 42.64 (t, C-11), 42.15

(t, C-18), 31.12 (t, C-6), 26.38 (t, C-1⁰), 24.03 (t, C-5), 23.00 (q, C-8),

22.82 (q, C-9), 11.22 (q, C-10).

This compound was prepared in quantitative yield according to

the previous published literature [3a] (the analytical and spectro-

scopic data were identical).

4.27. (3R,4R)-3-(2-(dibenzylamino)ethyl)-4,7,7-trimethyl-1⁰,3⁰-

dihydrospiro[heptane[2.2.1]heptanes-2,2⁰-inden]-3-ol (39)

To a stirred solution of 37 (0.050 g, 0.17 mmol) in THF/H₂O

(3 ml/0.5 ml) were added K₂CO₃(0.07 g, 0.50 mmol) and benzylbr-

omide (0.086 g, 0.5 mmol) at room temperature. The reaction mix-

ture was reﬂuxed for 1.5 h. The reaction was quenched with H₂O

and extracted with Et₂O. The organic extract was dried over anhy-

drous Na₂SO₄and the solvent evaporated in vacuo. The crude prod-

uct was puriﬁed by column chromatography

(U = 13 mm,

h = 220 mm, 8 g silica gel, hexane:Et₂O = 50:1) to give 0.068 g,

4.24. 2-((1R,2R)-2-hydroxy-1,3,3-trimethylbicyclo[2.2.1]heptan-2-

yl)acetonitrile (36)

(85%) of 39 as a colorless oil. ½a _D²⁰

ꢂ

= +19.7 (c 1.46, CHCl₃). Anal. Calc.

for C₃₄H₄₁NO (479.70): C, 85.13; H, 8.61; N, 2.92. Found: C, 85.17;

H, 8.59; N, 2.95%. MS (EI) m/z (rel. int.): 479 (M⁺ꢀ, 36), 210 (100),

198 (16), 106 (20), 81 (87). ¹H NMR (600 MHz, CDCl₃, 300 K) d:

7.19–7.13 (m, 5H, Ar), 7.09–7.01 (m, 4H, Ar), 6.95–6.91 (m, 5H,

Ar), 4.06 (d, 1H, 18-H_a, J = 16.2 Hz), 3.10 (d, 2H, 3⁸-H, J = 13.8 Hz),

3.01 (s, 2H, 11-H), 2.99 (d, 2H, 3⁸-H, J = 13.8 Hz), 2.70 (d, 1H, 18-

To a solution of 1.94 g (47.30 mmol) dry CH₃CN in 50 ml THF

was added at ꢀ80 °C 15.75 ml (39.40 mmol) 2.5 M solution of n-

BuLi in hexane (after stirring for 45 min at this temperature, a

white precipitate was formed). To the mixture was added 3.00 g

G.M. Dobrikov et al. / Polyhedron 45 (2012) 126–143

141

H_b, J = 16.2 Hz), 2.24–2.21 (m, 1H, 2⁰-H_a), 2.18–2.14 (m, 1H, 2⁰-H_b),

1.79–1.74 (m, 1H, 1⁰-H_a), 1.70–1.67 (m, 1H, 1⁰-H_b), 1.60 (d, 1H, 4-H,

J = 4.3 Hz), 1.53–1.48 (m, 1H, 5-H_exo), 1.43–1.39 (m, 1H, 5-H_endo),

1.31–1.36 (m, 1H, 6-H_endo), 1.29 (s, 3H, 8-H), 1.22–1.17 (m, 1H,

6-H_exo), 0.80 (s, 3H, 9-H), 0.75 (s, 3H, 10-H). ¹³C NMR (600 MHz,

CDCl₃, 300 K) d: 145.41 (s, 1 arom. C), 143.14 (s, 1 arom. C),

136.34 (s, 1 arom. C), 129.75 (d, 1 arom. C), 128.13 (d, 1 arom.

C), 127.10 (d, 1 arom. C), 126.22 (d, 1 arom. C), 125.79 (d, 1 arom.

C), 124.19 (d, 1 arom. C), 122.92 (d, 1 arom. C), 85.96 (s, C-2), 60.65

(s, C-3), 59.33 (d, C-4), 55.42 (s, C-1), 55.23 (t, C-3⁸), 51.39 (t, C-2⁰),

48.56 (s, C-7), 43.56 (t, C-11), 43.06 (t, C-18), 29.67 (t, C-6), 27.89 (t,

C-1⁰), 24.16 (t, C-5), 23.02 (q, C-8), 23.00 (q, C-9), 12.01 (q, C-10).

1.71–1.68 (m, 1H, 1⁰-H_b), 1.66 (d, 1H, 4-H, J = 4.4 Hz), 1.60–1.55

(m, 1H, 5-H_exo), 1.50–1.42 (m, 2H, 5-H_endo, 6-H_endo), 1.30 (s, 3H,

8-H), 1.29–1.25 (m, 1H, 6-H_exo), 0.873 (s, 3H, 10-H), 0.867 (s, 3H,

9-H), 0.66 (t, 6H, 4⁰-H, J = 7.2 Hz). ¹³C NMR (600 MHz, CDCl₃,

300 K) d: 145.41 (s, 1 arom. C), 143.06 (s, 1 arom. C), 125.97 (d, 1

arom. C), 125.71 (d, 1 arom. C), 124.17 (d, 1 arom. C), 122.87 (d,

1 arom. C), 85.89 (s, C-2), 60.46 (s, C-3), 59.59 (d, C-4), 55.45 (s,

C-1), 50.32 (t, C-3⁰), 48.51 (s, C-7), 45.28 (t, C-2⁰), 43.63 (t, C-11),

43.20 (t, C-18), 29.65 (t, C-6), 27.73 (t, C-1⁰), 24.08 (t, C-5), 22.96

(q, C-8, C-9), 11.95 (q, C-10), 10.41 (q, C-4⁰).

4.30. (1R,2R)-2-(2-(dibenzylamino)ethyl)-1,3,3-

trimethylbicyclo[2.2.1]heptan-2-ol (42)

4.28. (3R,4R)-3-(2-(isoindolin-2-yl)ethyl)-4,7,7-trimethyl-1⁰,3⁰-

dihydrospiro[bicyclo[2.2.1]heptane-2,2⁰-inden]-3-ol (40)

To a solution of 0.48 g (2.41 mmol) 38 in 40 ml THF and 4 ml

water were added 1.03 g (7.50 mmol) K₂CO₃and 2.48 g

(14.50 mmol) benzylbromide. The resulting mixture was reﬂuxed

for 3 h and the reaction was monitored by TLC (hex-

ane:Et₂O = 20:1). After cooling, the solvent was evaporated in va-

cuo. The residue was diluted with 150 ml water and extracted

with Et₂O. The organic phase was washed 2 times with water, dried

over anhydrous K₂CO₃and the solvent was evaporated in vacuo.

The crude product was puriﬁed by column chromatography

To a stirred solution of 37 (0.098 g, 0.33 mmol) in THF/H₂O

(6 ml/1 ml) were added K₂CO₃(0.137 g, 0.99 mmol) and

a,

a⁰-di-

chloro-o-xylene (0.075 g, 0.43 mmol) at room temperature. The

reaction mixture was reﬂuxed for 10 h (the reaction progress was

monitored by TLC). The reaction was quenched with H₂O and ex-

tracted with Et₂O. The organic extract was dried over anhydrous

Na₂SO₄and the solvent evaporated in vacuo. The crude product

was puriﬁed by column chromatography

(

U

= 12 mm,

(U = 20 mm, h = 280 mm, 40 g silica gel, (a) hexane, (b) hex-

h = 280 mm, 13 g silica gel, hexane/Et₂O = 5:1), to give 0.114 g,

ane:Et₂O = 50:1) to give 0.74 g (81%) 42 as white crystals. Mp

(86%) of 40 as a waxy solid. ½a _D²⁰

ꢂ

= 0 (c 1.28, CHCl₃). Anal. Calc.

49–50 °C. ½a ²_D⁰

= ꢀ28.6 (c 0.44, CHCl₃). Anal. Calc. for C₂₆H₃₅NO

ꢂ

for C₂₈H₃₅NO (401.58): C, 83.74; H, 8.78; N, 3.49. Found: C,

83.79; H, 8.74; N, 3.53%. MS (EI) m/z (rel. int.): 401 (M⁺ꢀ, 53), 132

(100), 118 (46), 105 (29). ¹H NMR (600 MHz, CDCl₃, 300 K) d:

7.19–7.13 (m, 4H, arom. H), 7.11–7.10 (m, 2H, arom. H), 7.05–

7.03 (m, 2H, arom. H), 4.07 (d, 1H, 18-H_a, J = 16.1 Hz), 3.64 (d,

1H, 3⁰-H, J = 11.9 Hz), 3.29 (d, 1H, 3⁰-H, J = 11.9 Hz), 3.12 and 3.09

(d, AB-system, 2H, 11-H, J = 16.6 Hz), 2.75 (d, 1H, 18-H_b,

J = 16.1 Hz), 2.53 (dt, 1H, 2⁰-H_a, J = 12.9, 4.1 Hz), 2.40–2.36 (m,

1H, 2⁰-H_b), 1.89–1.82 (m, 2H, 1⁰-H), 1.69 (d, 1H, 4-H, J = 4.3 Hz),

1.63–1.57 (m, 1H, 5-H_exo), 1.53–1.44 (m, 2H, 5-H_endo, 6-H_endo),

1.34–1.28 (m, 1H, 6-H_exo), 1.28 (s, 3H, 8-H), 0.92 (s, 3H, 10-H),

0.87 (s, 3H, 9-H). ¹³C NMR (600 MHz, CDCl₃, 300 K) d: 145.48 (s,

1 arom. C), 143.28 (s, 1 arom. C), 139.35 (s, 1 arom. C), 126.66 (d,

1 arom. C), 126.06 (d, 1 arom. C), 125.88 (d, 1 arom. C), 124.05

(d, 1 arom. C), 123.04 (d, 1 arom. C), 122.12 (d, 1 arom. C), 86.01

(s, C-2), 60.98 (s, C-3), 59.22 (d, C-4), 58.23 (t, C-3⁰), 55.43 (s, C-

1), 53.05 (t, C-2⁰), 48.62 (s, C-7), 43.64 (C-11), 43.13 (t, C-18),

29.79 (t, C-6), 29.36 (t, C-1⁰), 24.24 (t, C-5), 23.05 (q, C-9), 22.87

(q, C-8), 12.07 (q, C-10).

(377.56): C, 82.71; H, 9.34; N, 3.71. Found: C, 82.69; H, 9.34; N,

3.73%. MS (EI) m/z (rel. int.): 377 (M⁺ꢀ, 5), 308 (23), 295 (40), 286

(55), 210 (100), 197 (39), 181 (25), 106 (57), 91 (95). ¹H NMR

(600 MHz, CDCl₃, 300 K) d: 7.29–7.35 (m, 8H, 5⁸-H, 6⁸-H), 7.24–

7.28 (m, 2H, 7⁸-H), 6.07 (s, 1H, OH), 3.84 (d, 2H, 3⁸-H_a,

J = 13.1 Hz), 3.19 (d, 2H, 3⁸-H_b, J = 13.1 Hz), 2.91 (m, 1H, 2⁸-H_b),

2.53 (ddd, 1H, 2⁸-H_aJ = 13.0, 5.9, 2.4 Hz), 2.07 (m, 1H, 6-H_endo),

1.93 (ddd, 1H, 1⁸-H_b, J = 15.1, 11.1, 2.4 Hz), 1.59–1.67 (2H, 1⁸-H_a,

5-H_endo), 1.47 (m, 1H, 4-H), 1.43 (m, 1H, 7-H_syn), 1.30 (dddd, 1H,

5-H_exo, J = 12.5, 4.7 Hz), 0.98 (dd, 1H, 7-H_anti, J = 10.1, 1.6 Hz),

0.93 (s, 3H, 10-H), 0.86 (dt, 1H, 6-H_exo, J = 12.5, 4.3 Hz), 0.83 (s,

3H, 8-H), 0.43 (s, 3H, 9-H). _⁄¹³C NMR (600 MHz, CDCl₃, 300 K) d:

137.73 (s, 2C, 4⁸-C), 129.66 (d, 4C, 5⁸-C), 128.44^⁄(d, 4C, 6⁸-C),

127.33 (d, 2C, 7⁸-C), 82.10 (s, 1C, 2-C), 58.25 (t, 2C, 3⁸-C), 52.71 (s,

1C, 1-C), 51.49 (t, 1C, 2⁸-C), 50.37 (d, 1C, 4-C), 44.04 (s, 1C, 3-C),

40.62 (t, 1C, 7-C), 30.01 (t, 1C, 6-C), 28.94 (t, 1C, 1⁸-C), 27.88 (q,

1C, 8-C), 25.11 (t, 1C, 5-C), 22.49 (q, 1C, 9-C), 18.13 (q, 1C, 10-C).

4.31. (1R,2R)-2-(2-(isoindolin-2-yl)ethyl)-1,3,3-

trimethylbicyclo[2.2.1]heptan-2-ol (43)

4.29. (3R,4R)-3-(2-(diethylamino)ethyl)-4,7,7-trimethyl-1⁰,3⁰-

dihydrospiro[bicyclo[2.2.1]heptane-2,2⁰-inden]-3-ol (41)

To a solution of 0.50 g (2.53 mmol) 38 in 40 ml dioxane and

10 ml water were added 0.73 g (5.31 mmol) K₂CO₃and 0.89 g

To a stirred solution of 37 (0.170 g, 0.57 mmol) in THF/H₂O

(10 ml/1 ml) were added K₂CO₃(0.240 g, 1.70 mmol) and ethylio-

dide (0.265 g, 1.70 mmol) at room temperature. The reaction mix-

ture was reﬂuxed for 12 h (the reaction progress was monitored by

TLC). The reaction was quenched with H₂O and extracted with

Et₂O. The organic extract was dried over anhydrous Na₂SO₄and

the solvent evaporated in vacuo. The crude product was puriﬁed

(5.07 mmol) a,

a⁰-dichloro-o-xylene. The resulting mixture was re-

ﬂuxed for 7 h and the reaction was monitored by TLC (hex-

ane:Et₂O = 2:1). After cooling the mixture was diluted with

150 ml water and extracted with Et₂O. The organic phase was

washed 2 times with water, dried over anhydrous K₂CO₃and the

solvent was evaporated in vacuo. The crude product was puriﬁed

by column chromatography (

gel, hexane:Et₂O = 3:1) to give 0.28 g (37%) 43 as white crystals.

Mp 101–102 °C. = ꢀ26.7 (c 0.33, CHCl₃). Anal. Calc. for

₂₀H₂₉NO (299.45): C, 80.22; H, 9.76; N, 4.68. Found: C, 80.19; H,

U = 20 mm, h = 280 mm, 40 g silica

by column chromatography (U = 20 mm, h = 280 mm, 15 g silica

gel, hexane/Et₂O = 2:1), to give 0.079 g, (40%) of 41 as a colorless

½ ꢂ

a ²_D⁰

oil. ½a ²_D⁰

ꢂ

= +41.1 (c 0.48, CHCl₃). Anal. Calc. for C₂₄H₃₇NO (355.56):

C

C, 81.07; H, 10.49; N, 3.94. Found: C, 81.09; H, 10.53; N, 3.97%.

MS (EI) m/z (rel. int.): 355 (M⁺ꢀ, 10), 281 (23), 207 (67), 91 (42),

86 (100), 73 (51). ¹H NMR (600 MHz, CDCl₃, 300 K) d: 7.14–7.10

(m, 2H, Ar), 7.08–7.05 (m, 2H, arom. H), 4.13 (d, 1H, 18-H_a,

J = 16.3 Hz), 3.11 and 3.07 (AB-system, 2H, 11-H, J = 16.4 Hz),

2.76 (d, 1H, 18H_b, J = 16.3 Hz), 2.26–2.20 (m, 3H, 2⁰-H_a, 3⁰-H),

2.05–1.96 (m, 3H, 2⁰-H_b, 3⁰-H), 1.81–1.76 (m, 1H, 1⁰-H_a),

9.71; N, 4.69%. MS (EI) m/z (rel. int.): 299 (M⁺ꢀ, 6), 217 (24), 132

(100), 118 (52), 105 (22). ¹H NMR (600 MHz, CDCl₃, 300 K) d:

7.17 (m, 4H, 5⁸-H, 6⁸-H, 7⁸-H, 8⁸-H), 6.67 (br s, 1H, OH), 4.06 (d,

2H, 3⁸-H_a, J = 11.3 Hz), 3.90 (d, 2H, 3⁸-H_b, J = 11.3 Hz), 3.19 (m, 1H,

2⁸-H_b), 2.94 (dddd, 1H, 2⁸-H_a, J = 12.5, 8.4, 5.4, 2.9 Hz), 2.09 (dddd,

1H, 6-H_endo, J = 12.3, 7.3, 4.9, 2.3 Hz), 1.85 (m, 1H, 1⁸-H_b), 1.66–

1.73 (m, 2H, 1⁸-H_a, 5-H_endo), 1.59 (m, 1H, 4-H), 1.53 (dq, 1H, 7-H_syn

,

142

G.M. Dobrikov et al. / Polyhedron 45 (2012) 126–143

(g) K. Mikami, M. Lautens, New Frontiers in Asymmetric Catalysis, Wiley-

Interscience, Hoboken, 2007;

(h) R.G. Arrays, J. Adrio, J.C. Carretero, Angew. Chem., Int. Ed. 45 (2006) 7674;

(i) V. Dimitrov, K. Kostova, Lett. Org. Chem. 3 (2006) 176.

[2] (a) M. Kitamura, S. Suga, K. Kawai, R. Noyori, J. Am. Chem. Soc. 108 (1986)

6071;

J = 10.1, 4.0, 2.3 Hz), 1.36 (ddt, 1H, 5-H_exo, J = 12.6, 9.4, 4.4 Hz), 1.10

(s, 3H, 8-H), 1.07 (s, 3H, 10-H), 1.06 (m, 1H, 1H, 7-H_anti), 1.02 (s, 3H,

9-H), 0.90 (dt, 1H, 6-H_exo, J = 12.3, 4.4 Hz). ¹³C NMR (600 MHz,

CDCl₃, 300 K) d: 139.39 (s, 2C, 4⁸-C), 126.79 (d, 2C, 5⁸-C, 8⁸-C),

122.19 (d, 2C, 6⁸-C, 7⁸-C), 81.88 (s, 1C, 2-C), 58.92 (t, 2C, 3⁸-C),

54.46 (t, 1C, 2⁸-C), 52.77 (s, 1C, 1-C), 50.49 (d, 1C, 4-C), 44.50 (s,

1C, 3-C), 40.81 (t, 1C, 7-C), 30.83 (t, 1C, 1⁸-C), 30.08 (t, 1C, 6-C),

28.14 (q, 1C, 8-C), 25.05 (t, 1C, 5-C), 23.44 (q, 1C, 9-C), 18.15 (q,

1C, 10-C).

(b) M. Kitamura, S. Okada, S. Suga, R. Noyori, J. Am. Chem. Soc. 111 (1989)

4028;

(c) R. Noyori, S. Suga, K. Kawai, S. Okada, M. Kitamura, N. Oguni, M. Hayashi, T.

Kaneko, Y. Matsuda, J. Organomet. Chem. 382 (1990) 19;

(d) M. Kitamura, S. Suga, M. Niwa, R. Noyori, J. Am. Chem. Soc. 117 (1995)

4832;

(e) M. Yamakawa, R. Noyori, J. Am. Chem. Soc. 117 (1995) 6327;

(f) M. Yamakawa, R. Noyori, Organometallics 18 (1999) 128;

(g) R. Noyori, Angew. Chem., Int. Ed. 41 (2002) 2008.

[3] (a) W.A. Nugent, Chem. Commun. (1999) 1369;

(b) Y.K. Chen, A.M. Costa, P.J. Walsh, J. Am. Chem. Soc. 123 (2001) 5378;

(c) V. Dimitrov, G. Dobrikov, M. Genov, Tetrahedron: Asymmetry 12 (2001)

1323;

4.32. (8R,10R)-7,13,13-trimethyldispiro[1,3-oxazaperhydroine-6,2⁰-

bicyclo[2.2.1]heptane-3⁰,2⁰⁰-indane] (44)

To a stirred solution of 37 (0.166 g, 0.56 mmol) in 0.5 ml formic

acid, 0.3 ml 40% aqueous solution of formaldehyde was added at

room temperature and the mixture was reﬂuxed for 1.5 h (the

reaction progress was monitored by TLC). The reaction was

quenched with 10% aqueous solution of NaOH and extracted with

Et₂O. The organic extract was dried over anhydrous Na₂SO₄and the

solvent evaporated in vacuo. The crude product was puriﬁed by

(d) M. Genov, K. Kostova, V. Dimitrov, Tetrahedron: Asymmetry 8 (1997)

1869;

(e) I. Philipova, V. Dimitrov, S. Simova, Tetrahedron: Asymmetry 10 (1999)

1381;

(f) A.G. Martinez, E.T. Vilar, A.G. Fraile, S. de la Moya Cerero, B.L. Maroto,

Tetrahedron Lett. 46 (2005) 3509;

(g) N. Hanyu, T. Aoki, T. Mino, M. Sakamoto, T. Fujita, Tetrahedron: Asymmetry

11 (2000) 4127;

(h) N. Hanyu, T. Aoki, T. Mino, M. Sakamoto, T. Fujita, Tetrahedron:

Asymmetry 11 (2000) 2971;

(i) Y. Kasashima, N. Hanyu, T. Aoki, T. Mino, M. Sakamoto, T. Fujita, J. Oleo Sci.

54 (2005) 495;

(j) R.W. Parrott Ii, S.R. Hitchcock, Tetrahedron: Asymmetry 19 (2008) 19;

(k) A.G. Martinez, E.T. Vilar, A.G. Fraile, S. de la Moya Cerero, P. Martinez-Ruiz,

P.C. Villas, Tetrahedron: Asymmetry 13 (2002) 1;

(l) T. de las Casas Engel, B.L. Maroto, A.G. Martinez, S. de la Moya Cerero,

Tetrahedron: Asymmetry 19 (2008) 2003.;

column chromatography (

U = 17 mm, h = 380 mm, 20 g silica gel,

CH₂Cl₂/CH₃OH = 100:1), to give 0.120 g, (67%) of 44 as colorless

crystals. Mp 75–76 °C ½a _D²⁰

= ꢀ23.7 (c 0.27, CHCl₃). Anal. Calc. for

ꢂ

C

₂₂H₃₁NO (325.49): C, 81.18; H, 9.60; N, 4.30. Found: C, 81.09; H,

9.53; N, 4.27%. MS (EI) m/z (rel. int.): 325 (M⁺ꢀ, 100), 216 (30),

142 (35), 129 (24), 115 (23), 71 (69). ¹H NMR (600 MHz, CDCl₃,

300 K) d: 7.15–7.10 (m, 4H, arom. H), 4.00 (dd, 1H, 3⁰-H_a, J = 9.2,

2.2 Hz), 3.58 (d, 1H, 18-H_a, J = 17.0 Hz), 3.43 (d, 1H, 3⁰-H_b,

J = 9.2 Hz), 3.17 and 3.04 (AB-system, 2H, 11-H, J = 16.9 Hz), 2.88

(d, 1H, 18-H_b, J = 17.0 Hz), 2.54–2.52 (m, 1H, 2⁰-H_a), 2.07 (s, 3H,

N-CH₃), 2.02–1.94 (m, 2H, 2⁰-H_b, 1⁰-H_a), 1.69 (d, 1H, 4-H,

J = 4.7 Hz), 1.66–1.57 (m, 2H, 1⁰-H_b, 5-H_exo), 1.53–1.43 (m, 2H, 5-

(m) Q.Y. Xu, T.X. Wu, X.F. Pan, Chin. Chem. Lett. 12 (2001) 1055;

(n) D. Le Goanvic, M. Holler, P. Pale, Tetrahedron: Asymmetry 13 (2002) 119;

(o) Q. Xu, G. Wang, X. Pan, A.S.C. Chan, Tetrahedron: Asymmetry 12 (2001)

381;

(p) Y. Hari, T. Aoyama, Synthesis (2005) 583;

(q) W. Oppolzer, R.N. Radinov, Tetrahedron Lett. 29 (1988) 5645;

(r) A.G. Martinez, E.T. Vilar, A.G. Fraile, S. de la Moya Cerero, B.L. Maroto,

Tetrahedron: Asymmetry 14 (2003) 1959;

(s) M. Knollmuller, M. Ferencic, P. Gartner, Tetrahedron: Asymmetry 10 (1999)

3969.

H_endo, 6-H_endo), 1.29 (s, 3H, 8-H), 1.25–1.20 (m, 1H, 6-H_exo), 0.93

(s, 3H, 10-H), 0.89 (s, 3H, 9-H). ¹³C NMR (600 MHz, CDCl₃, 300 K)

d: 144.66 (s, 1 arom. C), 142.25 (s, 1 arom. C), 126.51 (d, 1 arom.

C), 126.28 (d, 1 arom. C), 123.81 (d, 1 arom. C), 123.36 (d, 1 arom.

C), 86.30 (s, C-2), 82.01 (t, C-3⁰), 61.37 (d, C-4), 59.80 (s, C-3), 56.83

(s, C-1), 49.10 (t, C-2⁰), 48.16 (s, C-7), 44.52 (t, C-18), 42.97 (t, C-11),

38.87 (q, C-4⁰), 29.08 (t, C-6), 24.78 (t, C-1⁰), 23.89 (t, C-5), 22.92 (q,

C-8, C-9), 11.72 (q, C-10).

[4] (a) B. Goldfuss, M. Steigelmann, S.I. Khan, K.N. Houk, J. Org. Chem. 65 (2000)

77;

(b) A.G. Martinez, E.T. Vilar, A.G. Fraile, S. de la Moya Cerero, P. Martinez-Ruiz,

Tetrahedron: Asymmetry 13 (2002) 1457;

(c) B. Goldfuss, M. Steigelmann, F. Rominger, Eur. J. Org. Chem. (2000) 1785;

(d) A.G. Martinez, E.T. Vilar, A.G. Fraile, S. de la Moya Cerero, P. Martinez-Ruiz,

C. Diaz Morillo, Tetrahedron: Asymmetry 18 (2007) 742;

(e) A.G. Martinez, E.T. Vilar, A.G. Fraile, S. de la Moya Cerero, B.L. Maroto,

Tetrahedron: Asymmetry 15 (2004) 753;

Acknowledgements

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[5] (a) A. Hui, J. Zhang, H. Sun, Z. Wang, Arkivoc 2 (2008) 25;

(b) A. Hui, J. Zhang, J. Fan, Z. Wang, Tetrahedron: Asymmetry 17 (2006) 2101;

(c) C.D. Hwang, B.J. Uang, Tetrahedron: Asymmetry 9 (1998) 3979;

(d) D.J. Ramon, M. Yus, Tetrahedron: Asymmetry 8 (1997) 2479;

(e) D.J. Ramon, M. Yus, Synlett (2007) 2309;

(f) V.J. Forrat, Ramon, D.J. Ramon, M. Yus, Tetrahedron: Asymmetry 17 (2006)

2054.

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Singaram, J. Org. Chem. 74 (2009) 2337;

Financial support of the National Science Fund, Bulgaria

(DID02/33/2009 and DRNF02/1), and MU0135/2008, is gratefully

acknowledged We also thank the staff of the NMR department of

the Institute of Organic Chemistry with Centre of Phytochemistry

for performing the NMR experiments.

Appendix A. Supplementary data

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CCDC 871586 and 871585 contains the supplementary crystal-

lographic data for Rp-15 and Sp-18, respectively. These data can be

obtained free of charge via http://www.ccdc.cam.ac.uk/conts/

retrieving.html or from the Cambridge Crystallographic Data Cen-

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Article Doi

Functionalized organolithium reagents in the synthesis of chiral ligands for catalytic enantioselective addition of diethylzinc to aldehydes

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