A novel type of chiral triangulane-based diphosphane ligands for transition metals

FULL PAPER

DOI: 10.1002/ejoc.201101715

A Novel Type of Chiral Triangulane-Based Diphosphane Ligands for

Transition Metals^[‡]

Alexander F. Khlebnikov,^[a]Sergei I. Kozhushkov,^[b]Dmitry S. Yufit,^[c]Heiko Schill,^[b]

Michael Reggelin,^[d]Volker Spohr,^[d]and Armin de Meijere*^[b]

Keywords: Phosphane ligands / Spiro compounds / Small ring systems / Cyclopropanes

A new original strategy for the synthesis of axially and heli-

cally chiral bidentate diphosphane ligands featuring a rigid

triangulanyl backbone has been elaborated and executed for

several representative enantiomerically pure ligands. Thus,

and

(1R,3R,4R,5R)-1,5-bis(diphenylphosphanyl)dispiro-

[2.0.2.1]heptane [(1R,3R,4R,5R)-36·(BH₃)₂] with a spiropentyl

and a dispiro[2.0.2.1]heptyl moiety, respectively, have been

prepared as bishydroborane complexes applying repetitively

(1R,3S,4S)-1,4-bis[(diphenylphosphanyl)methyl]spiro[2.2]pent- the same set of standard synthetic operations, starting from

ane [(1R,3S,4S)-24·(BH₃)₂], [(1R,3R,4S)-4-(diphenylphosphan- [(1S,3R)-4-methylenespiropent-1-yl]methyl acetate [(1S,3R)-

yl)methylspiro[2.2]pentan-1-yl]diphenylphosphane [(1R,3R,4S)- 7], (4,4-dibromospiropent-1-yl)methanols [(1S,3R)-8 and

27·(BH₃)₂], [(1R,3R,4S,5R)-5-(diphenylphosphanyl)methyldi-

spiro[2.0.2.1]heptan-1-yl]diphenylphosphane [(1R,3R,4S,5R)-

30·(BH₃)₂], (1S,3S,4S)-1,4-bis(diphenylphosphanyl)spiropent-

ane [(1R,3S,4S)-35·(BH₃)₂], (1S,3S,4S)-1,4-bis(diphenylphos-

phanyl)spiropentane [(1S,3S,4S)-35·(BH₃)₂], (1S,3S,4S)-1,4-

bis(diphenylphosphanyl)spiropentane [(1R,3R,4S)-35·(BH₃)₂],

(1R,3S)-8] and (dibromodispiro[2.0.2.1]heptyl)methanols

(1R,3S,4R)-9, (1S,3R,4S)-9 and (1S,3R,4R)-9 in 4–7 steps. The

relative configurations of all important intermediates as well

as the absolute configurations of the key intermediates and

most final products were established by X-ray crystal struc-

ture analyses.

palladium-catalyzed cross couplings.^[5]Employing a more

compact rigid scaffold than a cyclopentane, such as a three-

membered ring, would reduce the conformational flexibility

of the catalytically active metallacycles without introducing

additional steric demands. This, for appropriate rigid chiral

structures, might help to control the stereochemical out-

come of the reactions. Indeed, enantiomerically pure cyclo-

propane-containing ligands have been efficiently employed

in asymmetric alkyl- and dialkylzinc additions to carbonyl

groups,^[6]in asymmetric hydrogenations^[7]and 1,4-additions

of arylboronic acids to prochiral cycloalkenones,^[8]in asym-

metric allylic alkylations,^[9]in the cyclopropanation and cy-

clopropenation of alkenes and alkynes, respectively,^[10]in

Heck couplings^[11]and other reactions. The preparation and

application of a cyclopropane analogue of Tedicyp, all-cis-

1,2,3-tris(diphenylphosphanylmethyl)cyclopropane (2) (in

short TriCyp-PPP), has also been reported.^[12]

Introduction

Transition metal-catalyzed transformations are indis-

pensable tools in synthetic organic chemistry.^[2,3]One of the

most important endeavors in this chemistry is the develop-

ment of new bulky and electron-rich mono- and oligodent-

ate ligands for different coupling reactions,^[3]and the efforts

of a number of synthetic groups around the world have

been focused on this problem. Among the better ligands are

small carbocyclic skeletons with two or more diarylphos-

phanyl or other heteroatomic groups attached in geminal

or vicinal positions. For example, the so-called Tedicyp [cis,

cis,cis-1,2,3,4-tetrakis(diphenylphosphanylmethyl)cyclo-

pentane (1)] ligand elaborated by Santelli et al.^[4]demon-

strated extremely high turnover numbers (TON) in Negishi-

(TON up to 800000) and Heck-type (TON up to 66000)

[‡] See ref.^[1]

[a] Department of Chemistry, Saint Petersburg State University,

Universitetskii Prosp. 26, Petrodvorets, 198504 St. Petersburg,

Russia

[b] Institut für Organische und Biomolekulare Chemie der Georg-

August-Universität Göttingen,

Tammannstrasse 2, 37077 Göttingen, Germany

Fax: +49-551-399475

E-mail: ameijer1@uni-goettingen.de

[c] Department of Chemistry, University of Durham,

South Rd., Durham DH1 3L, UK

[d] Clemens-Schöpf-Institut für Organische Chemie und Biochemie

der Technischen Universität Darmstadt,

Petersenstraße 22, 64287 Darmstadt, Germany

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New Chiral Triangulane-Based Diphosphane Ligands

Another interesting group of completely rigid skeletons anes 8 and 9, and the stereochemical outcome of these reac-

that comes to mind as a potential ligand platform includes tions appeared to be of prime importance. Among a

the highly strained so-called linear [n]triangulanes 3, hydro- number of reported reagents for such reductions,^[13b,15a]tri-

carbons that consist of spiroannelated cyclopropane rings butyltin hydride as introduced by Seyferth et al.^[15b]almost

only.^[13]Herein we describe the realization of this idea and half a century ago, turned out to be the most reliable one

present the design of a new type of chiral bidentate diphos- for gem-dibromotriangulanes.^[15c]

phane ligands represented by 4–6 (n = 2, 3) featuring rigid

triangulanyl backbones, which might lead to novel, highly

efficient catalytic systems for various reactions.

Results and Discussion

1. Preparation of the New Ligands

The actual starting materials for the preparation of di-

phosphane ligands 4–6 (n = 2, 3) were the previously de-

scribed enantiomerically pure [(1S,3R)-4-methylenespiro-

pent-1-yl]methyl acetate (1S,3R)-7 as well as (4,4-dibromo-

spiropent-1-yl)methanols (1S,3R)-8 and (1R,3S)-8, which

were obtained by means of enantioselective enzymatic

acetylation catalyzed by Lipase PS^®(Pseudomonas sp) or

Scheme 2. Retrosynthetic considerations for bidentate diphosphane

ligands 4–6.

enantioselective enzymatic deacetylation with Lipase CES,

respectively.^[14]Compounds 4–6 (n = 3) were synthesized

from (1S,3R,4S)- and (1S,3R,4R)-(5,5-dibromodispiro-

[2.0.2.1]heptyl)methanols (1S,3R,4S)-9 and (1S,3R,4R)-9,

which in turn were obtained from (1S,3R)-7 according to

the previously published protocol^[14a,14b]in 32 and 28%

yield, respectively (Scheme 1). The enantiomer (1R,3S,4R)-

9 was prepared analogously.^[14a,14b]

To start with, the relative configurations of diastereomers

formed upon monohydrodebromination of racemic (rac-

4,4-dibromospiropent-1-yl)methanol rac-8 with tributyltin

hydride were determined. Towards that goal, the two oily

products 13 isolated by column chromatography in 41 and

32% yield, respectively, were converted into their crystalline

3,5-dinitrobenzoates (Scheme 3). The relative configura-

tions of both diastereomers of rac-13 could be assigned on

the basis of an X-ray crystal structure analysis,^[16]which

Scheme 1. Starting materials for the synthesis of bidentate diphos-

phane ligands 4–6. Reagents and conditions: a) CHBr₃, KOH (pel-

lets), BnEt₃N⁺Cl^–, CH₂Cl₂, 20–25 °C, 1–3 h; b) MeOH, H₂SO₄,

65 °C, 4 h.

Our goal was to elaborate a linear strategy to approach

any enantiomerically pure diphosphane ligand 4–6 by repet-

itively applying the same set of standard synthetic opera-

tions on the same set of precursors (Scheme 2). According

to this approach, the key step in these preparations would

Scheme 3. Monohydrodebromination of 4,4-dibromospiropent-1-

ylmethanols 8 and determination of the relative configurations of

products. Reagents and conditions: a) nBu₃SnH, Et₂O, 20 °C, 6 h;

be the monohydrodebromination of the dibromotriangul- b) 3,5-dinitrobenzoyl chloride, Py, 20 °C, 2 h, then 4 °C, 15 h.

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A. de Meijere et al.

FULL PAPER

was performed for an arbitrarily selected 3,5-dinitrobenzo- the absolute configurations of bromo[3]triangulanes

ate 14 of the second eluted (4-bromospiropent-1-yl)meth- (1S,3R,4R,5R)-15 and (1S,3R,4R,5S)-15, obtained from di-

anol 13. The latter bore the (1RS,3SR,4RS)-configuration. bromo[3]triangulane (1S,3R,4R)-9 in 36 and 20% yield,

Accordingly, the first and the second eluted enantiomers, respectively, as well as of bromo[2]triangulanes (1R,3S,4R)-

obtained upon hydrodebromination of enantiomerically 13 and (1R,3S,4S)-13, obtained from dibromo[2]triangul-

pure dibromide (1S,3R)-8 in 34 and 47% yield, respectively, ane (1R,3S)-8 in 37 and 44% yield, respectively, were estab-

had to have the absolute configurations (1S,3R,4R)-13 and lished by X-ray crystal structure analyses^[16]of the acids

(1S,3R,4S)-13, respectively, as concluded from the results of (1S,3R,4R,5R)-17 and (1R,3S,4S)-18. The latter were ob-

the X-ray crystal structure analysis and the known absolute tained by oxidation of the bromotriangulanemethanols

configuration of the starting material (1S,3R)-8 (Scheme 3). (1S,3R,4R,5R)-15 and (1R,3S,4S)-13 with in situ-generated

By analogy, the absolute configurations of monobrom- ruthenium tetroxide^[17]in 72 and 77% yield, respectively

ides (1R,3S,4R,5R)-15 and (1R,3S,4R,5S)-15, obtained (Scheme 4).

from dibromo[3]triangulane (1R,3S,4R)-9 in 60 and 39%

The flexible ligand (1R,3S,4S)-24 (ϵ 4, when n = 2) with

yield, respectively, under the same conditions, were derived

a syn,anti-arrangement of its (diphenylphosphanyl)-

from the X-ray crystal structure analysis^[16]of an arbitrarily methyl groups was synthesized from the tetrahydropyranyl

selected 3,5-dinitrobenzoate (1R,3S,4R,5S)-16 prepared ether (1R,3S,4S)-19, prepared in 93% yield from the corre-

from (1R,3S,4R,5S)-15 (Scheme 4). In contrast to this, sponding bromospiropentylmethanol (1R,3S,4S)-13. The

ether (1R,3S,4S)-19 was converted into bis(hydroxymethyl)-

spiropentane (1R,3S,4S)-22 in three simple steps, i.e. carb-

oxylation, reduction and deprotection, in 81% overall yield

(Scheme 5). Subsequent conversion to the dibromide with

triphenylphosphane dibromide,^[18]ensuing treatment with

lithium diphenylphosphide^[19]and then BH₃·THF com-

plex^[20]furnished the bisborane complex of the ligand

(1R,3S,4S)-24·(BH₃)₂as a glass in 39% overall yield start-

ing from bromospiropentylmethanol (1R,3S,4S)-13

(Scheme 5).

Scheme 5. Synthesis of the flexible bidentate chiral ligand

(1R,3S,4S)-24 and the precursor (1R,3S,4R)-22 to (1R,3S,4R)-24.

Scheme 4. Monohydrodebromination of (5,5-dibromodispiro-

[2.0.2.1]heptyl)methanols (1R,3S,4R)-9 and (1S,3R,4R)-9 and de-

termination of the absolute configurations of products. Reagents

and conditions: a) nBu₃SnH, Et₂O, 20 °C, 6 h; b) 3,5-dinitro-

benzoyl chloride, Py, 20 °C, 2 h, then 4 °C, 15 h; c) RuCl₃·H₂O,

NaIO₄, MeCN/CCl₄/H₂O, 0–20 °C, 1.75 h.

Reagents and conditions: a) DHP, PPTS, CH₂Cl₂, 20 °C, 6.5 h;

b) tBuLi, Et₂O, –78 °C, 1 h, then CO₂(solid), –78 to 20 °C, 1 h;

c) LiAlH₄, Et₂O, 34 °C, 1 h; d) MeOH, PPTS, 65 °C, 1 h;

e) PPh₃·Br₂, Py, CH₂Cl₂, –30 to 20 °C, 5.5 h; f) Ph₂PH, nBuLi,

THF, 0 °C, 0.5 h, then (1R,3S,4S)-23, 0 °C, 0.5 h, then BH₃·THF,

0 °C, 0.5 h.

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New Chiral Triangulane-Based Diphosphane Ligands

Obviously, this synthetic approach can also be employed ylphosphane) ligands of type 5 (n = 2, 3). As the two brom-

for the preparation of the diastereomeric flexible ligand ine substituents in 25 and 28 are vastly different in reacti-

(1R,3S,4R)-24 with an anti,anti-arrangement of (diphenyl- vity, they can consecutively be replaced with diphenylphos-

phosphanyl)methyl groups. However, this sequence was car- phanyl groups under different conditions. Nucleophilic dis-

ried out only up to the bis(hydroxymethyl)spiropentane placement in 25 and 28 with lithium diphenylphosphide^[19]

(1R,3S,4R)-22 (Scheme 5).

and trapping with borane-tetrahydrofuran leads to the

The hydroxymethyl group in the intermediates 13 or 15 monophosphane–borane complexes 26·BH₃and 29·BH₃,

can easily be converted to a bromomethyl group by treat- respectively. Treatment in situ of the latter with n-butyllith-

ment with triphenylphosphane–bromine reagent.^[18]Thus, ium and then chlorodiphenylphosphane^[9a,21]furnished the

the bromospiropentylmethanols (1S,3R,4R)-13 and ligands (1R,3R,4S)-27·(BH₃)₂and (1R,3R,4S,5R)-30·

(1R,3S,4R,5R)-15 afforded the bromospiropentylmethyl (BH₃)₂in 35 and 15% overall yield, respectively (Scheme 6).

bromides (1R,3R,4S)-25 and (1R,3R,4S,5R)-28 in 91 and The absolute configurations of the final products

83% yield, respectively (Scheme 6). The latter can directly (1R,3R,4S)-27·(BH₃)₂and (1R,3R,4S,5R)-30·(BH₃)₂as well

be used to prepare the chiral triangulane-based bis(diphen- as that of the intermediate (1S,3R,4R)-26·BH₃were as-

signed on the basis of the known absolute configurations

of the respective starting materials and confirmed by X-ray

crystal structure analyses.^[16]

The starting materials for the preparation of chiral bi-

dentate ligands of type 6 were obtained from the acids 17

and 18 employing Barton’s modification of the Hunsdiecker

reaction, i.e. one-pot preparation and photolytic fragmenta-

tion in BrCCl₃at 0 °C of the corresponding Barton thio-

hydroxamic esters (Scheme 7).^[22]This transformation had

previously proved to be applicable to cyclopropanecarbox-

ylic acids.^[23]Thus, under the published conditions, the acid

(1S,3R,4S)-18 [prepared analogously to (1R,3S,4S)-18 in

90% yield, see Exp. Sect.] afforded a 1:1.4 mixture (NMR)

of diastereomeric dibromides (1R,3R,4S)-31 and

(1S,3R,4S)-31 in 68% yield. These dibromides turned out

to be inseparable by column chromatography, but could be

isolated by HPLC in only 18 and 26% yield, respectively.

Their relative configurations were established on the basis

of their NMR spectra. In view of the higher symmetry of

compound (1S,3R,4S)-31, corresponding H and C atoms

in the two cyclopropane rings are magnetically equivalent,

Scheme 6. Synthesis of chiral bidentate ligands of type

[(1R,3R,4S)-27 and (1R,3R,4S,5R)-30]. Reagents and conditions:

5

a) PPh₃·Br₂, Py, CH₂Cl₂, –30 to 20 °C, 5.5 h; b) Ph₂PH, nBuLi, Scheme 7. Synthesis of enantiomerically pure 1,4-dibromospi-

THF, 0 °C, 0.5 h, then (1R,3R,4S)-25 or (1R,3R,4S,5R)-28, 0 °C,

0.5 h, then BH₃·THF, 0 °C, 0.5 h; c) tBuLi, Et₂O, –78 °C, 0.3 h,

then Ph₂PCl, –78 to 0 °C, 1 h, then BH₃·THF, 0 °C, 0.5 h.

ropentanes 31 and 1,5-dibromo[3]triangulanes 32. Reagents and

conditions: a) 2-sulfanylpyridine N-oxide, DCC, DMAP, BrCCl₃,

20 °C, 5 h, then hν, 0 °C, 1.5 h.

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1

therefore the H- and ¹³C-NMR spectra of this compound

are very simple and show only three types of signals each

for protons and carbon atoms. The absolute configurations

were assigned on the basis of the known absolute configura-

tions of the acid starting materials. The acid (1R,3S,4S)-18

afforded

a

mixture of diastereomeric dibromides

(1S,3S,4S)-31 and (1R,3S,4S)-31 which, in contrast to the

previous case, were easily separated by column chromatog-

raphy and isolated in 19 and 49% yield, respectively. At

last, the dibromides (1S,3R,4R,5R)-32 and (1R,3R,4R,5R)-

32 obtained from the acid (1S,3R,4R,5R)-17 in 43 and 31%

yield, respectively, could only be separated by repeated col-

umn chromatography because of their very close R_fvalues.

Their relative configurations could be determined on the

basis of their NMR spectra due to the higher symmetry of

the dibromide (1R,3R,4R,5R)-32 (see Exp. Sect.).

Surprisingly, an attempted twofold phosphanylation of

the dibromide (1S,3R,4S)-31 at –78 °C under conditions

employed above (Scheme 6) completely failed, and the bor-

ane complex of tert-butyldiphenylphosphane (33) was the

sole product isolated in 99% yield [Scheme 8, conditions

(a)]. This can be attributed to a competing side reaction

wherein the intermediate dilithiospiropentane would dehy-

drobrominate the by-product tert-butyl bromide to yield

isobutene at this temperature.^[24]

Bromine-lithium exchange on (1R,3S,4S)-31 with tert-

butyllithium at lower temperature (–110 °C), subsequent

phosphanylation employing a larger excess of reagents in

each step and prolonged reaction time for the lithiation

[Scheme 8, conditions (b)] furnished a mixture of diastereo-

meric (bromospiropentyl)diphenylphosphanes (1S,3S,4R)-

34·BH₃and (1R,3S,4S)-34·BH₃along with the enantio-

merically pure bidentate ligand (1R,3S,4S)-35·(BH₃)₂,

which were isolated as their borane complexes by flash col-

umn chromatography as a solid, an oil and a glass, respec-

tively, in 9, 34 and 14% yield, respectively. The absolute

configurations of the monophosphanes 34 were assigned on

the basis of an X-ray crystal structure analysis^[16]of the

compound (1S,3S,4R)-34·BH₃.

In view of the result of the latter lithiation/phosphanyl-

ation sequence, the experiment was repeated with even

larger excesses of reagents (7.5 equiv. of each tert-butyllith-

ium and chlorodiphenylphosphane for each bromine atom)

[Scheme 8, conditions (c)] to furnish only the target com-

pound (1R,3S,4S)-35·(BH₃)₂in 37% yield along with the

by-product 33. These optimized conditions were employed

for the preparation of two more chiral bidentate ligands of

type 6 from the enantiomerically pure 1,4-dibromospi-

ropentanes (1S,3S,4S)-31 and (1R,3R,4S)-31 as well as from

1,5-dibromo[3]triangulane (1R,3R,4R,5R)-32. The former

afforded the corresponding ligand (1S,3S,4S)-35·(BH₃)₂

Scheme 8. Synthesis of enantiomerically pure bidentate ligands of

type 6 [(1R,3S,4S)-35·(BH₃)₂, (1S,3S,4S)-35·(BH₃)₂, (1R,3R,4S)-

35·(BH₃)₂and (1R,3R,4R,5R)-36·(BH₃)₂]. Reagents and condi-

tions: a) tBuLi (3.9 equiv.), Et₂O, –78 °C; then Ph₂PCl (2.25 equiv.),

–78 to 20 °C, 1 h; then BH₃·THF, 0 °C, 1 h; b) tBuLi (6.0 equiv.),

Et₂O, –110 °C, 1 h; then Ph₂PCl (6.0 equiv.), –110 to 20 °C, 2.5 h;

then BH₃·THF, 0 °C, 1 h c) tBuLi (15.0 equiv.), Et₂O, –110 °C, 1 h;

then Ph₂PCl (15.0 equiv.), –110 to 20 °C, 3 h; then BH₃·THF, 0 °C,

1 h.

2. Preliminary Examination of the New Ligands

The allylic substitution of 1,3-diphenyl-2-propenyl acet-

very cleanly and in an unexpectedly high yield (80%), while ate (37) with the enolate of dimethyl malonate (38)

the yields of (1R,3R,4S)-35·(BH₃)₂and (1R,3R,4R,5R)- (Scheme 9), which has become a standard reaction for

36·(BH₃)₂were only 32 and 28%, respectively. The abso- evaluating catalysts for enantioselective allylations of 1,3-

lute configuration of (1S,3S,4S)-35·(BH₃)₂and of dicarbonyl compounds,^[25]was arbitrarily selected for a pre-

(1R,3R,4R,5R)-36·(BH₃)₂were assigned on the basis of the liminary evaluation of the potentially beneficial features of

known absolute configurations of the starting materials, and these new triangulanyl ligands for asymmetrically induced

they were confirmed by X-ray crystal structure analyses.^[16]

transformations (Scheme 9).

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New Chiral Triangulane-Based Diphosphane Ligands

Table 1. Pd⁰-catalyzed asymmetric allylic alkylation of 37 with di-

methyl malonate (38) employing enantiomerically pure triangulane

ligands

(1R,3S,4S)-24,

(1R,3R,4S)-27,

(1R,3R,4S,5R)-30,

(1S,3S,4S)-35, (1R,3S,4S)-35, (1R,3R,4S)-35 and (1R,3R,4R,5R)-

36 (see Scheme 9).

Scheme 9. Examination of the new ligands in the asymmetrically

induced allylation of the allyl acetate 37 with malonate 38. Rea-

gents and conditions: {Pd[η³-(C₃H₅)]Cl}₂, (10 mol-%), ligand

(10 mol-%), O,N-bis(trimethylsilyl)acetamide (BSA), CH₂Cl₂,

20 °C. For details see Table 1.

With most of the tested ligands, the reactions were com-

plete within 5 minutes or less (see Table 1), indicating ex-

traordinarily high catalytic activities of palladium com-

plexes derived from the ligands (1R,3S,4S)-24, (1R,3R,4S)-

27, (1R,3R,4S,5R)-30, (1R,3R,4S)-35 and (1R,3R,4R,5R)-

36. However, in most cases the achieved enantioselectivities

turned out to be only moderate or low. The highest enantio-

meric excess (78%) was obtained with the ligand

(1R,3R,4S)-35. For comparison, various types of chiral

N,P-ligands provided ee-values of up to 99% in this reac-

tion,^[25e]and the cyclopropyl-containing [(S,S,R)-(–)-2-(1-

methylsulfanylethyl)cyclopropyl]diphenylphosphane^[9a]gave

the product 39 in high yield and with good enantio-

selectivity (ee 93%). To test the effect of the reaction tem-

perature^[25b]on the above allylation reaction, it was per-

formed in the presence of the best ligand (1R,3R,4S)-35 at

–20 and –40 °C for 12 and 40 h, respectively, to furnish 39

in 79 and 18% yield, respectively, with ee of 80 and 78%,

respectively. Apparently, the characteristic isoinversion tem-

perature^[28,29]for this reaction does not fall into the tem-

perature interval from –40 to +22 °C.

The different performances of the new ligands must be

associated with the different structural features. According

to the structural examinations,^[16]the distances between two

phosphorus atoms in the crystalline ligands (1S,3S,4S)-

35·(BH₃)₂,

(1R,3R,4R,5R)-36·(BH₃)₂,

(1R,3R,4S)-27·

(BH₃)₂and (1R,3R,4S,5R)-30·(BH₃)₂in the solid state vary

from 4.464 to 5.329, 5.905 and 6.373 Å, respectively. With

ee values of 14, 45, 34 and 13% in this sequence (Table 1)

[a] Time required for quantitative conversion according to TLC.

[b] Isolated yields. [c] As determined by integration of the methoxy

there is no apparent simple correlation with the P···P dis- groups signals in ¹H-NMR spectra in the presence of europium-

(III) tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorate]

tances. However, in view of their limited degree of flexibility

due to the rigid triangulane fragments in these ligand back-

bones, the corresponding transition metal complexes should

[Eu(hfc)₃, 20 mol-%].^[26][d] Configuration of the excess enantiomer

as determined by comparison with previously published results.^[27]

be conformationally constrained systems with marked steric

effects and distinct catalytic activities. With different P···P bite angle (101–102°), for (1R,3S,4S)-24, which are all close

distances and different flexibilities, these ligands would lead to the proposed optimum of around 102° for the bite angle

to vastly different bite angles in the catalytically active com- in palladium complexes catalyzing allylic substitutions (and

plexes. To get an idea of these differences, bite angles for other reactions).^[35]These computed bite angles correlate to

assumed square planar palladium complexes of the synthe- a certain extent with the experimental results in that

sized ligands and PdCl₂were calculated using the PM3 there is an increase in the series (1R,3R,4S,5R)-30,

semi-empirical^[30,31]and density functional theory^[32,33](1R,3R,4R,5R)-36

methods as implemented in the SPARTAN program pack- (1R,3R,4S)-35 Ͼ (1S,3S,4S)-35 Ͼ (1S,3S,4S)-35 and a de-

age^[34](Table 2).

crease in enantioselectivity in the sequence (1R,3R,4S)-35

Ͼ

(1R,3S,4S)-24, (1R,3R,4S)-27,

In terms of predicted bite angles, the ligands fall into Ͼ (1R,3S,4S)-24, (1R,3S,4S)-35 ϾϾ (1R,3R,4R,5R)-36 Ͼ

three categories: very large (105–107°), for (1R,3R,4S)-27, (1R,3R,4S)-27 ϾϾ (1R,3R,4S,5R)-30, (1S,3S,4S)-35, that is

(1R,3R,4S,5R)-30, and (1R,3R,4R,5R)-36, large (ca. 98– noted with increasing bite angles. Only ligand (1R,3S,4S)-

100°), for the three diastereomers of 35 and an intermediate 24 presents an exception to this general trend, since both

Eur. J. Org. Chem. 2012, 1530–1545

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1535

A. de Meijere et al.

FULL PAPER

Table 2. P···P-distances and bite angles for palladium complexes of the new chiral bidentate ligands from semi-empirical PM3 and DFT

(closed shell, B3LYP/LACVP+* level of theory) calculations.

PM3

RB3LYP/LACVP+*

P–Pd–P angle

Entry

Ligand

d(P···P) /Å

P–Pd–P angle

d(P···P) /Å

1

2

3

4

5

6

7

(1R,3S,4S)-24

(1R,3R,4S)-27

(1R,3R,4S,5R)-30

(1S,3S,4S)-35

(1R,3S,4S)-35

(1R,3R,4S)-35

(1R,3R,4R,5R)-36

3.51

3.67

3.66

3.43

3.46

3.45

3.66

101°

107°

98.0°

98.2°

97.7°

107°

3.69

3.84

3.77

3.53

3.62

3.85

102°

107°

105°

99.2°

99.3°

99.6°

107°

ether and THF were obtained by distillation from sodium benzo-

phenone ketyl, anhydrous pyridine and CH₂Cl₂by distillation from

calcium hydride. All other chemicals were used as commercially

available. Organic extracts were dried with MgSO₄. NMR spectra

were recorded with Bruker AM 250 (250 MHz for ¹H and

62.9 MHz for ¹³C NMR), Bruker DPX 300 (300.13 MHz for ¹H

and 75.54 MHz for ¹³C NMR), Varian VXR Inova 500 S

(500.13 MHz for ¹H and 125.71 MHz for ¹³C NMR) and Varian

Inova 600 (599.8 MHz for ¹H and 150.8 MHz for ¹³C NMR) in-

struments in CDCl₃, if not otherwise specified. Multiplicities were

determined by DEPT (Distortionless Enhancement by Polarization

Transfer) measurements. Chemical shifts refer to δ_TMS= 0.00 ac-

cording to the chemical shifts of residual CHCl₃signals. IR spectra

were recorded with a Bruker IFS 66 FT-IR on KBr pellets or oils

between NaCl plates. Mass spectra were measured with a Finnigan

MAT 95 (EI and HR-EI, at 70 eV, using preselected ion peak

matching at R ϾϾ 10000 to be within Ϯ2 ppm of the exact masses;

DCI, at 200 eV, reactant gas NH₃), Finnigan LCQ (ESI) and

Bruker Daltonic APEX IV 7T FTICR (ESI-HRMS) spectrometers.

Preparative HPLC separation of compounds (1R,3R,4S)-31 and

(1S,3R,4S)-31 was performed using a column with Kromasil RP18

(MeOH/H₂O, 7:3). Optical rotations were measured with a Perkin–

Elmer 241 digital polarimeter in a 1 dm cell. Melting points were

determined on a Büchi 510 capillary melting point apparatus. TLC

analyses were performed on precoated sheets, 0.25 mm Sil G/UV₂₅₄

(Macherey–Nagel). Silica gel grade 60 (230–400 mesh) (Merck) was

used for column chromatography.

the reactivity and the enantioselectivity are enhanced in its

presence. This finding supports the above mentioned con-

cept of an optimal bite angle, which is best represented by

this ligand. The only other exception observed was with

(1S,3S,4S)-35, which afforded the lowest enantioselectivity

of all, although this ligand has the smallest predicted bite

angle.

Conclusions

In conclusion, a newly developed synthetic strategy was

successively employed to furnish enantiomerically pure di-

phosphane ligands of types 4–6 (n = 2, 3) featuring rigid

triangulane backbones. By this approach, several represen-

tative ligands were obtained as crystals [(1R,3R,4S)-

27·(BH₃)₂, (1R,3R,4S,5R)-30·(BH₃)₂, (1S,3S,4S)-35·(BH₃)₂

and (1R,3R,4R,5R)-36·(BH₃)₂], which – in the form of their

respective borane complexes – could be subjected to X-ray

crystal structure analyses.^[16]Three more, namely

(1R,3S,4S)-24·(BH₃)₂(1R,3S,4S)-35·(BH₃)₂and (1R,3R,4S)-

35·(BH₃)₂, were isolated as glasses only.

Essentially the same strategy should be applicable for the

preparation of triangulane-based bidentate ligands of types

40-X, 41-X and 42-X with one phosphorus and one other

heteroatom (e.g. X = OR, SR, NR₂). Analogous mixed cy-

clopropane-based chiral ligands with two types of hetero-

atoms in appropriate transition metal complexes have dem-

onstrated extraordinary activities in a number of catalyzed

organic reactions.^[6,9a,11]Further efforts to apply this strat-

egy towards the synthesis of these interesting ligands of

types 40–42 as well as further examination of the synthe-

sized chiral triangulane-based bisphosphanes as ligands in

various transition metal-catalyzed reactions are clearly war-

ranted.

General Procedure for the Monohydrodebromination of the Di-

bromides rac-8, (1S,3R)-8, (1R,3S)-8 and (1R,3S,4R)-9 (GP1): To a

solution of the respective dibromotriangulane (20 mmol) in anhy-

drous diethyl ether (20 mL), a solution of tributyltin hydride

(21 mmol) in Et₂O (10 mL) was added under cooling with ice over

a period of 5 min. The reaction mixture was stirred at ambient

temperature for 6 h, the products were distilled off into a cold trap

at 65–70 °C/1 mbar for bromides 13 or at 100 °C/0.001 mbar for

bromides 15 and then separated by column chromatography on

silica gel.

[(1RS,3SR,4RS)- and (1RS,3SR,4SR)-4-Bromospiro[2.2]pent-1-yl]-

methanol [(1RS,3SR,4RS)-13 and (1RS,3SR,4RS)-13]: Column

chromatography [325 g of silica gel, eluent pentane/Et₂O (2:1), GC

monitoring] of the distillate obtained from [(1RS,3SR)-4,4-di-

bromospiro[2.2]pent-1-yl]methanol (rac-8) (5.12 g, 20 mmol) and

nBu₃SnH (6.11 g, 21 mmol) according to GP1 afforded

(1RS,3SR,4RS)-13 (1.44 g, 41%, first eluted) and (1RS,3SR,4SR)-

13 (1.14 g, 32%, second eluted) as colorless oils. Bromide

Experimental Section

General Remarks: Racemic (rac-4,4-dibromospiropent-1-yl)meth-

anol (rac-8), enantiomerically pure [(1S,3R)-4-methylenespiropent-

1-yl]methyl acetate [(1S,3R)-7], (4,4-dibromospiropent-1-yl)meth-

anols [(1S,3R)-8 and (1R,3S)-8], (dibromodispiro[2.0.2.1]heptyl)-

methanols (1R,3S,4R)-9, (1S,3R,4S)-9 and (1S,3R,4R)-9 were pre-

pared according to previously published protocols.^[14]3,5-Dini-

trobenzoyl chloride was recrystallized twice from diethyl ether and

then from hexane. All operations in anhydrous solvents were per-

formed under argon in flame-dried glassware. Anhydrous diethyl

1

(1RS,3SR,4RS)-13: H NMR (250 MHz, CDCl₃): δ = 1.00 (t, J =

5.0 Hz, 1 H, cPr-H), 1.27 (dd, J = 3.3, 6.0 Hz, 1 H, cPr-H), 1.32

(dd, J = 4.6, 8.1 Hz, 1 H, cPr-H), 1.46–1.60 (m, 2 H, cPr-H +

OH), 3.31 (dd, J = 3.3, 6.5 Hz, 1 H, CHBr), 3.60–3.68 (m, 2 H,

CH₂O) ppm. ¹³C NMR (62.9 MHz, CDCl₃): δ = 13.4 (CH₂), 13.9

1536

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Eur. J. Org. Chem. 2012, 1530–1545

New Chiral Triangulane-Based Diphosphane Ligands

(CH₂), 20.7 (CH), 21.0 (C), 22.7 (CH), 65.1 (CH₂) ppm. C₆H₉BrO

(177.04): calcd. C 40.71, H 5.12; found C 40.92, H 5.26. Bromide

(1RS,3SR,4SR)-13: H NMR (250 MHz, CDCl₃): δ = 0.87 (t, J =

H, CHBr), 3.56–3.72 (m, 2 H, CH₂O) ppm. ¹³C NMR (62.9 MHz,

CDCl₃): δ = 10.1 (CH₂), 11.7 (CH₂), 16.1 (CH₂), 19.1 (CH), 21.6

1

(C), 21.9 (C), 22.3 (CH), 66.0 (CH₂) ppm. (1S,3R,4R,5R)-15 7: H

4.7 Hz, 1 H, cPr-H), 1.13 (dd, J = 3.2, 8.2 Hz, 1 H, cPr-H), 1.20 NMR (250 MHz, CDCl₃): δ = 0.69 (t, J = 4.6 Hz, 1 H, cPr-H),

(dd, J = 3.3, 5.8 Hz, 1 H, cPr-H), 1.53–1.58 (m, 2 H, cPr-H + OH), 1.16 (dd, J = 3.5, 6.0 Hz, 1 H, cPr-H), 1.33 (d, J = 4.2 Hz, 1 H,

1.65–1.77 (m, 1 H, cPr-H), 3.31 (ddd, J = 1.0, 3.3, 6.9 Hz, 1 H, cPr-H), 1.39 (d, J = 4.4 Hz, 1 H, cPr-H), 1.38–1.46 (m, 3 H, cPr-

CHBr), 3.48–3.64 (m, 2 H, CH₂O) ppm. ¹³C NMR (62.9 MHz,

H, OH), 3.50 (dd, J = 3.5, 6.9 Hz, 1 H, CHBr), 3.59–3.73 (m, 2 H,

CDCl₃): δ = 11.5 (CH₂), 14.0 (CH₂), 21.1 (C), 22.1 (CH), 22.8 CH₂O) ppm. ¹³C NMR (62.9 MHz, CDCl₃): δ = 7.5 (CH₂), 11.8

(CH), 64.7 (CH₂) ppm. C₆H₉BrO (177.04): calcd. C 40.71, H 5.12; (CH₂), 15.8 (CH₂), 18.2 (C), 18.5 (CH), 20.9 (C), 25.3 (CH), 65.7

found C 40.98, H 5.18.

(CH₂) ppm.

[(1S,3R,4R)- and (1S,3R,4S)-4-Bromospiro[2.2]pent-1-yl]methanol

General Procedure for the Preparation of 3,5-Dinitrobenzoates

[(1S,3R,4R)-13 and (1S,3R,4S)-13]: Column chromatography [600 g (1RS,3SR,4SR)-14, (1RS,3SR,4RS)-14, (1R,3S,4R,5S)-16 and

of silica gel, eluent pentane/Et₂O (2:1), GC-monitoring] of the dis-

tillate obtained from dibromide (1S,3R)-8 (15.36 g, 60 mmol) and

nBu₃SnH (18.34 g, 61 mmol) according to GP1 afforded

(1S,3R,4R)-13 (3.58 g, 34%, first eluted) and (1S,3R,4S)-13 (5.01 g,

47%, second eluted) as colorless oils. Their ¹H and ¹³C NMR spec-

tra were identical with those of the racemic compounds

(1RS,3SR,4RS)-13 and (1RS,3SR,4SR)-13.

(1R,3S,4R,5R)-16 (GP2): To a solution of the respective bromotri-

angulanylmethanol (0.5 mmol) in anhydrous pyridine (5 mL) was

added 3,5-dinitrobenzoyl chloride (DNBC, 0.8 mmol), and the re-

action mixture was stirred at ambient temperature for 2 h, then left

at +4 °C overnight. The resulting mixture was poured into ice-cold

water and extracted with diethyl ether (3ϫ 20 mL); the combined

organic layers were washed with aq. 10% HCl solution, then with

aq. 0.5 n NaHCO₃solution and brine (20 mL each). After drying

and removal of the solvents under reduced pressure, the residue

was recrystallized to furnish the respective dinitrobenzoate as a col-

orless solid.

[(1R,3S,4S)- and (1R,3S,4R)-4-Bromospiro[2.2]pent-1-yl]methanol

[(1R,3S,4S)-13 and (1R,3S,4R)-13]: Column chromatography in

two portions [600 g of silica gel each, eluent pentane/Et₂O (2:1),

GC monitoring] of the distillate obtained from dibromide (1R,3S)-

8 (31.45 g, 123 mmol) and nBu₃SnH (37.6 g, 129 mmol) according

to GP1 afforded (1R,3S,4S)-13 (9.55 g, 44%, first eluted) and

[(1RS,3SR,4SR)-4-Bromospiro[2.2]pent-1-yl]methyl

3,5-Dinitro-

benzoate [(1RS,3SR,4SR)-14]: After recrystallization from diethyl

(1R,3S,4R)-13 (8.13 g, 37%, second eluted) as colorless oils. Their ether/hexane, (1SR,3RS,4RS)-14 (105 mg, 50%) was obtained from

¹H and ¹³C NMR spectra were identical with those of racemic com-

pounds (1RS,3SR,4RS)-13 and (1RS,3SR,4SR)-13.

bromo alcohol (1SR,3RS,4RS)-13 (100 mg, 0.565 mmol) and

DNBC (186 mg, 0.806 mmol) according to GP2, m.p. 85–86 °C. ¹H

NMR (300 MHz, CDCl₃): δ = 1.17 (t, J = 5.1 Hz, 1 H, cPr-H),

1.29 (dd, J = 2.7, 6.0 Hz, 1 H, cPr-H), 1.50 (dd, J = 5.0, 8.3 Hz, 1

H, cPr-H), 1.54–1.58 (m, 1 H, cPr-H), 1.73–1.85 (m, 1 H, cPr-H),

3.34 (dd, J = 3.3, 6.8 Hz, 1 H, CHBr), 4.22 (dd, J = 8.0, 11.2 Hz,

1 H, CH₂O), 4.65 (dd, J = 6.1, 11.2 Hz, 1 H, CH₂O), 9.16–9.18 (m,

2 H, Ar-H), 9.20–9.22 (m, 1 H, Ar-H) ppm. ¹³C NMR (62.9 MHz,

CDCl₃): δ = 14.1 (CH₂), 14.4 (CH₂), 17.5 (CH) 21.9 (C), 22.0 (CH),

69.7 (CH₂), 122.4 (2 CH), 129.5 (CH), 133.8 (C), 148.6 (2 C), 162.4

(C) ppm. C₁₃H₁₁BrN₂O₆(371.14): calcd. C 42.07, H 2.99, N 7.55;

found C 42.28, H 3.12, N 7.44.

[(1R,3S,4R,5R)- and (1R,3S,4R,5S)-5-Bromodispiro[2.0.2.1]hept-1-

yl]methanol 15 [(1R,3S,4R,5R)-15 and (1R,3S,4R,5S)-15]: Column

chromatography [500 g of silica gel each, eluent pentane/Et₂O (2:1),

GC monitoring] of the distillate obtained from dibromide

(1R,3S,4R)-9 (11.28 g, 40 mmol) and nBu₃SnH (12.22 g, 42 mmol)

according to GP1 afforded bromides (1R,3S,4R,5R)-15 (4.90 g,

60%, first eluted) and (1R,3S,4R,5S)-15 (3.30 g, 39%, second

eluted) as colorless oils. (1R,3S,4R,5R)-15: ¹H NMR (250 MHz,

CDCl₃): δ = 0.80 (t, J = 4.7 Hz, 1 H, cPr-H), 0.95 (dd, J = 4.7,

8.0 Hz, 1 H, cPr-H), 1.15 (dd, J = 3.5, 5.9 Hz, 1 H, cPr-H), 1.24

(d, J = 4.1 Hz, 1 H, cPr-H), 1.44 (d, J = 3.9 Hz, 1 H, cPr-H), 1.59 [(1RS,3SR,4RS)-4-Bromospiro[2.2]pent-1-yl]methyl

3,5-Dinitro-

(t, J = 6.5 Hz, 1 H, cPr-H), 1.72 (br.s., 1 H, OH), 1.88–2.07 (m, 1

H, cPr-H), 3.49 (dd, J = 3.5, 6.9 Hz, 1 H, CHBr), 3.52–3.71 (m, 2

H, CH₂O) ppm. ¹³C NMR (62.9 MHz, CDCl₃): δ = 9.6 (CH₂), 12.0

benzoate [(1RS,3SR,4RS)-14]: After recrystallization from CH₂Cl₂/

Et₂O/hexane, (1SR,3RS,4SR)-14 (130 mg, 62%) was obtained from

bromo alcohol (1SR,3RS,4SR)-13 (100 mg, 0.565 mmol) and

(CH₂), 15.8 (CH₂), 16.2 (CH), 18.3 (C), 20.7 (C), 25.3 (CH), 65.8 DNBC (186 mg, 0.806 mmol) according to GP2, m.p. 106–107 °C.

(CH₂) ppm. C₈H₁₁BrO (203.08): calcd. C 47.32, H 5.46; found C

47.51, H 5.39. (1R,3S,4R,5S)-15: ¹H NMR (250 MHz, CDCl₃): δ

= 0.73 (t, J = 4.8 Hz, 1 H, cPr-H), 0.83–0.92 (m, 1 H, cPr-H), 1.28–

1.42 (m, 5 H, cPr-H), 3.10 (dd, J = 3.7, 6.7 Hz, 1 H, CHBr), 3.50–

¹H NMR (300 MHz, CDCl₃): δ = 1.07 (t, J = 5.1 Hz, 1 H, cPr-H),

1.23–1.31 (m, 2 H, cPr-H), 1.57 (t, J = 7 Hz, 1 H, cPr-H), 1.90–

1.99 (m, 1 H, cPr-H), 3.32–3.36 (m, 1 H, CHBr), 4.32–4.42 (m, 2

H, CH₂O), 9.12–9.14 (m, 2 H, Ar-H), 9.20–9.23 (m, 1 H, Ar-

3.60 (m, 1 H, CH₂O), 3.68–3.77 (m, 1 H, CH₂O) ppm. ¹³C NMR H) ppm. ¹³C NMR (62.9 MHz, CDCl₃): δ = 12.4 (CH₂), 14.4

(62.9 MHz, CDCl₃): δ = 10.2 (CH₂), 11.8 (CH₂), 15.9 (CH₂), 19.1

(CH), 21.6 (C), 21.9 (C), 22.6 (CH), 65.7 (CH₂) ppm. C₈H₁₁BrO

(203.08): calcd. C 47.32, H 5.46; found C 47.25, H 5.58.

(CH₂), 18.7 (CH), 21.6 (C), 21.9 (CH), 69.3 (CH₂), 122.5 (CH),

129.5 (2 CH), 133.8 (C), 148.6 (2 C), 162.5 (C) ppm. C₁₃H₁₁BrN₂O₆

(371.14): calcd. C 42.07, H 2.99, N 7.55; found C 42.09, H 3.18, N

7.67. The relative configuration of the product was established by

X-ray crystal structure analysis.^[16]

[(1S,3R,4R,5R)- and (1S,3R,4R,5S)-5-Bromodispiro[2.0.2.1]hept-1-

yl]methanol [(1S,3R,4R,5R)-15 and (1S,3R,4R,5S)-15]: Column

chromatography in two portions [600 g of silica gel each, eluent

pentane/Et₂O (2:1), GC monitoring] of the distillate obtained from

dibromide (1S,3R,4R)-9 (25.38 g, 90 mmol) and nBu₃SnH (32.81 g,

94.5 mmol) according to GP1 afforded pure bromides

(1S,3R,4R,5R)-15 (6.63 g, 36%, first eluted), (1S,3R,4R,5S)-15

(8.13 g, 37%, second eluted) and a mixed fraction (3.25 g, 18%) as

(1R,3S,4R,5R)-[5-Bromodispiro[2.0.2.1]hept-1-yl]methyl 3,5-Dini-

trobenzoate [(1R,3S,4R, 5R)-16]: After recrystallization from di-

ethyl ether/hexane, (1R,3S,4R,5R)-16 (140 mg, 72%) was obtained

from bromo alcohol (1R,3S,4R,5R)-15 (100 mg, 0.492 mmol) and

DNBC (186 mg, 0.698 mmol) according to GP2, m.p. 67–68 °C,

1

[α]²_D⁵= –105.1 (c = 1.44, CHCl₃). H NMR (250 MHz, CDCl₃): δ

1

colorless oils. (1S,3R,4R,5S)-15: H NMR (250 MHz, CDCl₃): δ =

= 1.03 (t, J = 4.8 Hz, 1 H, cPr-H), 1.15 (dd, J = 5.1, 8.0 Hz, 1 H,

cPr-H), 1.22 (dd, J = 3.6, 6.1 Hz, 1 H, cPr-H), 1.37 (d, J = 4.3 Hz,

1 H, cPr-H), 1.50 (d, J = 4.2 Hz, 1 H, cPr-H), 1.64 (t, J = 6.5 Hz,

0.87 (t, J = 3.9 Hz, 1 H, cPr-H), 0.92 (dd, J = 4.7, 7.6 Hz, 1 H,

cPr-H), 1.30–1.42 (m, 6 H, cPr-H), 3.12 (ddd, J = 1.0, 3.6, 9.6 Hz, 1

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1537

A. de Meijere et al.

FULL PAPER

1 H, cPr-H), 2.17–2.88 (m, 1 H, cPr-H), 3.52 (dd, J = 3.5, 6.9 Hz,

m.p. 108–109 °C, [α]²_D⁵= –190.8 (c = 0.830, CHCl₃). ¹H NMR

1 H, CHBr), 4.41–4.56 (m, 2 H, CH₂O), 9.18–9.21 (m, 2 H, Ar-H), (250 MHz, CDCl₃): δ = 1.38 (dd, J = 4.0, 6.8 Hz, 1 H, cPr-H),

9.23–9.26 (m, 1 H, Ar-H) ppm. ¹³C NMR (62.9 MHz, CDCl₃): δ 1.68–1.74 (m, 2 H, cPr-H), 1.79 (t, J = 4.5 Hz, 1 H, cPr-H), 2.08

= 10.4 (CH₂), 12.1 (CH₂), 12.5 (CH) 15.8 (CH₂), 18.3 (C), 21.1 (C), (dd, J = 4.7, 8.4 Hz, 1 H, CH), 3.32 (dd, J = 3.9, 7.0 Hz, 1 H,

24.9 (CH), 70.0 (CH₂), 122.3 (CH), 129.5 (2 CH), 134.1 (C), 148.6

(2 C), 162.5 (C) ppm. C₁₅H₁₃BrN₂O₆(397.18): calcd. C 45.36, H

3.30, N 7.05; found C 45.53, H 3.45, N 7.18.

CHBr), 11.4 (br.s, 1 H, CO₂H) ppm. ¹³C NMR (62.9 MHz,

CDCl₃): δ = 15.8 (CH₂), 17.9 (CH₂), 21.6 (CH), 21.8 (CH), 26.1

(C), 179.7 (C) ppm. C₆H₇BrO₂(191.02): calcd. C 37.73, H 3.69;

found C 37.89, H 3.51. Its absolute configuration was established

by X-ray crystal structure analysis.^[16]

(1R,3S,4R,5S)-[5-Bromodispiro[2.0.2.1]hept-1-yl]methyl 3,5-Dini-

trobenzoate [(1R,3S,4R, 5S)-16]: After recrystallization from diethyl

ether/hexane, (1R,3S,4R,5S)-16 (170 mg, 87%) was obtained from

bromo alcohol (1R,3S,4R,5S)-15 (100 mg, 0.492 mmol) and DNBC

(1S,3R,4S)-4-Bromospiro[2.2]pentane-1-carboxylic Acid [(1S,3R,4S)-

18]: The acid (1S,3R,4S)-18 (2.04 g, 90%) was obtained from

bromo alcohol (1S,3R,4S)-13 (2.10 g, 11.86 mmol), NaIO₄

(12.684 g, 59.3 mmol) and RuCl₃·H₂O (267 mg, 1.19 mmol) accord-

(186 mg, 0.698 mmol) according to GP2, m.p. 78–79 °C, [α]²_D⁵

=

1

+102.4 (c = 1.36, CHCl₃). H NMR (250 MHz, CDCl₃): δ = 0.99

(t, J = 4.9 Hz, 1 H, cPr-H), 1.07 (dd, J = 5.1, 7.8 Hz, 1 H, cPr-H),

1.37–1.63 (m, 5 H, cPr-H), 3.13 (dd, J = 4.2, 7.5 Hz, 1 H, CHBr),

4.47–4.53 (m, 2 H, CH₂O), 9.18–9.19 (m, 2 H, Ar-H), 9.23–9.25

(m, 1 H, Ar-H) ppm. ¹³C NMR (62.9 MHz, CDCl₃): δ = 11.2

(CH₂), 11.9 (CH₂), 15.4 (CH), 16.1 (C), 21.6 (C), 22.1 (CH), 22.3

(CH₂), 70.2 (CH₂), 122.4 (CH), 129.5 (2 CH), 133.9 (C), 148.6 (2

C), 162.6 (C) ppm. C₁₅H₁₃BrN₂O₆(397.18): calcd. C 45.36, H 3.30,

N 7.05; found C 45.61, H 3.25, N 6.93. The absolute configuration

of the product was established by X-ray crystal structure analy-

sis.^[16]

1

ing to GP3, m.p. 76–78 °C, [α]²_D⁵= +246.9 (c = 1.040, CHCl₃). H

NMR (250 MHz, CDCl₃): δ = 1.46 (dd, J = 3.8, 6.8 Hz, 1 H, cPr-

H), 1.54 (dd, J = 4.4, 7.9 Hz, 1 H, cPr-H), 1.64–1.70 (m, 2 H, cPr-

H), 2.21 (dd, J = 4.5, 8.0 Hz, 1 H, CH), 3.39 (dd, J = 3.8, 7.2 Hz,

1 H, CHBr) ppm. ¹³C NMR (62.9 MHz, CDCl₃): δ = 15.8 (CH₂),

16.0 (CH₂), 22.0 (CH), 22.3 (CH), 25.9 (C), 178.9 (C) ppm. HRMS

(–ESI): calcd. for C₆H₆BrO₂[M – H]^–: 188.95567; found 188.95569.

General Procedure for the THP-Protection of Bromo Alcohols

(1R,3S,4S)-13 and (1R,3S,4R)-13 (GP4): A solution of the respec-

tive bromo alcohol (19 mmol), 3,4-dihydro-2H-pyran (DHP)

(35 mmol) and pyridinium p-toluene-4-sulfonate (PPTS)

(4.50 mmol) was stirred at ambient temperature for 6.5 h. The sol-

vent was removed under reduced pressure, and the residue was

purified by column chromatography (ca. 130 g of silica gel, eluent

pentane/Et₂O, 10:1) to afford the respective product as a colorless

oil.

General Procedure for the Oxidation of Bromotriangulanylmethanols

with in Situ Generated Ruthenium Tetroxide. Synthesis of the Acids

(1S,3R,4R,5R)-17, (1S,3R,4S)-18 and (1R,3S,4S)-18 (GP3): To a

solution of the respective bromo alcohol (34 mmol) in a mixture of

CCl₄(165 mL), acetonitrile (165 mL) and H₂O (220 mL) were

added under vigorous stirring and cooling with ice one after the

other NaIO₄(170 mmol) and RuCl₃·H₂O (3.4 mmol) in one por-

tion each. Vigorous stirring was continued at 0 °C for 15 min and

at ambient temperature for an additional 1.5 h; the reaction mix-

ture was diluted with CH₂Cl₂(200 mL) and filtered through a pad

of Celite. The aqueous layer was separated and extracted with

CH₂Cl₂(3ϫ 100 mL), the combined organic phases were washed

with brine (100 mL), dried and concentrated under reduced pres-

sure. The residue was dissolved in 0.2 m aq. Na₂CO₃solution (ca.

180 mL), and this solution was washed with diethyl ether (3ϫ

50 mL). The aqueous solution was cooled with ice and acidified

with conc. aq. HCl solution to pH ≈ 3 and extracted with diethyl

ether (3ϫ 50 mL), then with pentane (2ϫ 50 mL). The combined

extracts were dried and concentrated under reduced pressure. The

residue was recrystallized from diethyl ether/hexane to afford the

respective product as colorless crystals.

2-[(1R,3S,4S-4-Bromospiro[2.2]pentan-1-yl)methoxy]tetrahydro-2H-

pyran [(1R,3S,4S)-19]: Column chromatography of the residue ob-

tained from bromo alcohol (1R,3S,4S)-13 (3.50 g, 19.8 mmol),

DHP (2.94 g, 3.17 mL, 35 mmol) and PPTS (502 mg, 2.0 mmol)

according to GP4 afforded (1R,3S,4S)-19 (4.822 g, 93%). ¹H NMR

(250 MHz, CDCl₃): δ = 0.95–1.00 (m, 2 H, cPr-H), 1.18–1.35 (m,

4 H, cPr-H), 1.41–1.84 (m, 16 H, cPr-H, THP), 3.27 (dd, J = 3.3,

6.7 Hz, 1 H), 3.41 (dd, J = 7.2, 10.7 Hz, 1 H), 3.44–3.51 (m, 2 H),

3.54 (d, J = 6.7 Hz, 2 H), 3.69 (dd, J = 6.6, 10.7 Hz, 1 H), 3.80–

3.90 (m, 2 H), 4.61–4.64 (m, 1 H), 4.66–4.69 (m, 1 H) ppm. ¹³C

NMR (62.9 MHz, CDCl₃): δ = 14.0 and 14.1 (CH₂), 14.2 and 14

(CH₂), 18.1 and 18.5 (CH), 19.3 and 19.5 (CH₂), 20.8 and 21.0 (C),

22.9 and 23.1 (CH₂), 25.4 (CH₂), 30.55 and 30.58 (CH₂), 62.0 and

62.2 (CH₂), 69.6 and 69.9 (CH₂), 97.9 and 98.2 (CH) ppm.

2-[(1R,3S,4R-4-Bromospiro[2.2]pentan-1-yl)methoxy]tetrahydro-2H-

pyran [(1R,3S,4R)-19]: Column chromatography of the residue ob-

tained from bromo alcohol (1R,3S,4R)-13 (7.97 g, 45.0 mmol),

DHP (6.31 g, 6.8 mL, 75 mmol) and PPTS (1.130 g, 4.50 mmol)

according to GP4 afforded (1R,3S,4R)-19 (10.65 g, 91%). ¹H NMR

(250 MHz, CDCl₃): δ = 0.83 (t, J = 4.7 Hz, 2 H, cPr-H), 1.07–1.15

(m, 4 H, cPr-H), 1.45–1.76 (m, 16 H, cPr-H, THP), 3.21–3.29 (m,

3 H), 3.40–3.52 (m, 4 H), 3.63 (dd, J = 6.7, 10.5 Hz, 1 H), 3.71–

3.81 (m, 2 H), 4.48 (t, J = 3.1, 1 H), 4.55 (t, J = 3.3, 1 H) ppm.

¹³C NMR (62.9 MHz, CDCl₃): δ = 11.9 and 12.0 (CH₂), 14.2

(CH₂), 19.3 and 19.4 (CH₂), 21.26 and 21.37 (C), 19.79 and 19.83

(CH₂), 22.94 and 22.98 (CH), 25.3 and 30.5 (CH₂), 62.0 and 62.1

(CH₂), 69.7 and 70.0 (CH₂), 98.5 (CH) ppm.

5-Bromodispiro[2.0.2.1]heptanes-1-carboxylic Acid [(1S,3R,4R,5R)-

17]: The acid (1S,3R,4R,5R)-17 (5.012 g, 72%) was obtained from

bromo alcohol (1S,3R,4R,5R)-15 (6.529 g, 32.15 mmol), NaIO₄

(34.384 g, 161 mmol) and RuCl₃·H₂O (723 mg, 3.215 mmol) ac-

cording to GP3, m.p. 94–95 °C, [α]²_D⁵= +233.9 (c = 1.770, CHCl₃).

¹H NMR (250 MHz, CDCl₃): δ = 1.19 (dd, J = 3.7, 6.2 Hz, 1 H,

cPr-H), 1.45 (d, J = 5.0 Hz, 1 H, cPr-H), 1.53–1.58 (m, 1 H, cPr-

H), 1.62–1.64 (m, 2 H, cPr-H), 1.89–1.97 (m, 2 H, cPr-H), 3.47 (dd,

J = 3.6, 7.0 Hz, 1 H, CH), 11.93 (br.s, 1 H, CO₂H) ppm. ¹³C NMR

(62.9 MHz, CDCl₃): δ = 12.7 (CH₂), 13.3 (CH₂), 16.1 (CH₂), 19.5

(CH), 19.6 (C), 24.2 (CH), 26.4 (C), 180.3 (C) ppm. C₈H₉BrO₂

(217.06): calcd. C 44.27, H 4.18; found C 44.15, H 4.23. The abso-

lute configuration of the product was established by X-ray crystal

structure analysis.^[16]

General Procedure for the Bromine-Lithium Exchange and Subse-

quent Carboxylation of THP-Protected Bromo alcohols (1R,3S,4S)-

19 and (1R,3S,4R)-19 (GP5): A pentane solution of tBuLi

(1R,3S,4S)-4-Bromospiro[2.2]pentane-1-carboxylic Acid [(1R,3S,4S)-

18]: The acid (1R,3S,4S)-18 (4.98 g, 77%) was obtained from (40 mmol) was added dropwise to a solution of the respective THP-

bromo alcohol (1R,3S,4S)-13 (6.02 g, 34 mmol), NaIO₄(36.36 g, protected bromo alcohol (18.4 mmol) in anhydrous Et₂O (120 mL)

170 mmol) and RuCl₃·H₂O (766 mg, 3.4 mmol) according to GP3, at –78 °C over a period of 0.5–1 h. After stirring at this temperature

1538

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Eur. J. Org. Chem. 2012, 1530–1545

New Chiral Triangulane-Based Diphosphane Ligands

for an additional 1 h, powdered solid carbon dioxide (dry ice) (10 g)

was added in one portion. The reaction mixture was warmed up to

ambient temperature over a period of 1 h and then extracted with

water (100 mL). The aqueous solution was washed with diethyl

ether (2ϫ 50 mL), cooled with ice, acidified with 2 n aq. HCl solu-

tion to pH ≈ 3 and the mixture extracted with diethyl ether (3ϫ

70 mL), then with pentane (2ϫ 50 mL). The combined extracts

were dried and concentrated under reduced pressure. The residue

was used without further purification.

(7.577 g, 89%) was obtained from protected acid (1R,3S,4R)-20

(9.025 g, 39.89 mmol) and LiAlH₄(2.69 g, 70.1 mmol) according

1

to GP6 as an oil. H NMR (250 MHz, CDCl₃): δ = 0.54–0.62 (m,

2 H, cPr-H), 0.96–1.07 (m, 4 H, cPr-H), 1.41–1.82 (m, 18 H, cPr-

H, THP), 3.33–3.65 (m, 10 H), 3.74–3.86 (m, 2 H), 4.53–4.55 (m,

1 H), 4.59–4.62 (m, 1 H) ppm. ¹³C NMR (62.9 MHz, CDCl₃): δ =

8.20 and 8.25 (CH₂), 8.5 and 8.7 (CH₂), 16.0 and 16.1 (CH), 18.0

and 18.2 (C), 18.8 and 18.9 (CH), 19.4 and 19.5 (CH₂), 25.3 (CH₂),

30.5 and 30.6 (CH₂), 62.0 and 62.2 (CH₂), 66.0 (CH₂), 70.9 (CH₂),

98.4 and 98.5 (CH) ppm.

(1R,3S,4S)-4-[(Tetrahydro-2H-pyran-2-yloxy)methyl]spiro[2.2]pent-

ane-1-carboxylic Acid [(1R,3S,4S)-20]: The acid (1R,3S,4S)-20 General Procedure for the Deprotection of THP-Protected Diols

(3.62 g, 87 %) was obtained from the protected bromo alcohol

(1R,3S,4S)-21 and (1R,3S,4R)-21 (GP7): A solution of the respec-

tive mono-THP-protected diol (35 mmol) and pyridinium p-tolu-

ene-4-sulfonate (PPTS) (4.0 mmol) in MeOH (400 mL) was stirred

(1R,3S,4S)-19 (4.8 g, 18.38 mmol), tBuLi (40 mmol, 23 mL of

1

1.78 m solution) and dry ice (10 g) according to GP5 as an oil. H

NMR (250 MHz, CDCl₃): δ = 0.85–0.89 (m, 2 H, cPr-H), 1.14– under reflux with TLC monitoring for the indicated time. After

1.24 (m, 4 H, cPr-H), 1.32–1.38 (m, 2 H), 1.43–1.83 (m, 14 H), 1.95 cooling, water (0.5 mL) was added, and the reaction mixture was

(dd, J = 4.1, 7.5 Hz, 1 H), 3.33 (dd, J = 7.8, 10.6 Hz, 1 H), 3.42–

3.50 (m, 4 H), 3.65 (dd, J = 5.5, 10.5 Hz, 1 H), 3.80–3.87 (m, 2 H),

4.62–4.65 (m, 1 H), 4.66–4.69 (m, 1 H) ppm. ¹³C NMR (62.9 MHz,

CDCl₃): δ = 12.0 and 12.2 (CH₂), 13.4 and 13.7 (CH₂), 16.4 and

16.6 (CH), 19.3 and 19.4 (CH₂), 19.8 and 19.9 (CH), 22.5 and 22.9

(C), 25.4 (CH₂), 30.4 and 30.5 (CH₂), 62.1 and 62.2 (CH₂), 69.6

and 69.9 (CH₂), 98.6 and 98.5 (CH), 179.3 and 179.5 (C) ppm.

concentrated under reduced pressure. The residue was purified by

column chromatography (silica gel, eluent hexane/THF, 1:1) to af-

ford the product as a colorless oil.

(1R,3S,4S)-Spiro[2,4]pentane-1,4-diyldimethanol

[(1R,3S,4S)-22]:

Column chromatography of the residue obtained from THP-pro-

tected diol (1R,3S,4S)-21 (3.20 g, 15.1 mmol) and PPTS (502 mg,

2.0 mmol) according to GP7 (3 h reflux) afforded (1R,3S,4S)-22

(1.93 g, 100%), [α]²_D⁵= +25.7 (c = 0.755, CHCl₃). ¹H NMR

(250 MHz, CDCl₃): δ = 0.66 (t, J = 4.5 Hz, 1 H, cPr-H), 0.82 (t, J

(1R,3S,4R)-4-[(Tetrahydro-2H-pyran-2-yloxy)methyl]spiro[2.2]pent-

ane-1-carboxylic Acid [(1R,3S,4R)-20]: The acid (1R,3S,4R)-20

(9.025 g, 98 %) was obtained from protected bromo alcohol = 4.4 Hz, 1 H, cPr-H), 0.88 (dd, J = 4.4, 7.7 Hz, 1 H, cPr-H), 1.02

(1R,3S,4R)-19 (10.6 g, 40.6 mmol), tBuLi (89 mmol, 50 mL of

1.78 m solution) and dry ice (15 g) according to GP5 as an oil. H

(dd, J = 4.5, 7.9 Hz, 1 H, cPr-H), 1.39–1.50 (m, 2 H, cPr-H), 2.13

(s, 2 H, OH), 3.40 (dd, J = 8.0, 10.8 Hz, 1 H, CH₂OH), 3.57–3.72

1

NMR (250 MHz, CDCl₃): δ = 0.88 (t, J = 5.0 Hz, 2 H, cPr-H), (m, 2 H, CH₂OH), 3.76 (dd, J = 6.0, 10.8 Hz, 1 H, CH₂OH) ppm.

1.13–1.25 (m, 4 H, cPr-H), 1.41–1.82 (m, 14 H, cPr-H, THP), 1.94–

2.00 (m, 2 H), 3.34 (dd, J = 7.1, 10.5 Hz, 1 H), 3.42–3.60 (m, 6 H),

3.68 (dd, J = 6.9, 10.5 Hz, 1 H), 3.78–3.86 (m, 2 H), 4.55 (t, J =

3.3 Hz, 1 H), 4.60 (t, J = 3.3 Hz, 1 H) ppm. ¹³C NMR (62.9 MHz,

CDCl₃): δ = 10.2 and 10.3 (CH₂), 13.7 (CH₂), 17.88 and 17.93

(CH), 19.38 and 19.45 (CH₂), 19.8 (CH), 23.7 and 23.8 (C), 25.3

(CH₂), 30.5 (CH₂), 62.1 and 62.2 (CH₂), 70.1 and 70.2 (CH₂), 98.6

(CH), 179.91 and 179.95 (C) ppm.

¹³C NMR (62.9 MHz, CDCl₃): δ = 6.9 (CH₂), 10.0 (CH₂), 17.2

(CH), 17.6 (C), 18.3 (CH), 64.3 (CH₂), 66.4 (CH₂) ppm.

(1R,3S,4R)-Spiro[2,4]pentane-1,4-diyldimethanol [(1R,3S,4R)-22]:

Column chromatography of the residue obtained from THP-pro-

tected diol (1R,3S,4R)-21 (7.59 g, 35.8 mmol) and PPTS (1.0 g,

4.0 mmol) according to GP7 (18 h reflux) afforded (1R,3S,4R)-22

(4.58 g, 100%), [α]²_D⁵= –67.3 (c = 0.695, CHCl₃). ¹H NMR

(250 MHz, acetone-[D₆]): δ = 0.44–0.48 (m, 2 H, cPr-H), 0.97–1.02

(m, 2 H, cPr-H), 1.26–1.36 (m, 2 H, cPr-H), 3.34–3.52 (m, 4 H, 2

CH₂OH), 3.73 (t, J = 5.5 Hz, 2 H, 2 OH) ppm. ¹³C NMR

(62.9 MHz, [D₆]acetone): δ = 8.4 (2 CH₂), 19.0 (C), 19.9 (2 CH),

65.9(2 CH₂) ppm. C₇H₁₂O₂(128.17): calcd. C 65.60, H 9.44; found

C 65.78, H 9.62.

General Procedure for the Reduction of THP-Protected Acids

(1R,3S,4S)-20 and (1R,3S,4R)-20 (GP6): A solution of the respec-

tive acid (40 mmol) in anhydrous diethyl ether (70 mL) was added

dropwise to a suspension of LiAlH₄(71 mmol) in anhydrous Et₂O

(100 mL) at a rate leading to gentle boiling of the solvent. The

reaction mixture was stirred under reflux for an additional 23 h,

the reaction was quenched by careful addition of sat. aq. Na₂SO₄

solution, dried and concentrated under reduced pressure to furnish

the product as an oil which was used without further purification.

General Procedure for the Bromination of Alcohols and Diols

(1S,3R,4R)-13, (1R,3S,4R,5R)-15 and (1R,3S,4S)-22 (GP8): A solu-

tion of bromine (12.6 mmol) in anhydrous CH₂Cl₂(2 mL) was

added dropwise to a cooled (–15 °C), vigorously stirred solution of

PPh₃(12.6 mmol) in anhydrous CH₂Cl₂(70 mL) at –15 °C. After

additional stirring for 0.5 h, a solution of the respective alcohol

(12 mmol) or diol (6 mmol) and anhydrous pyridine (0.95 g,

0.97 mL, 12 mmol) in CH₂Cl₂(5 mL) was added dropwise at

–30 °C. The reaction mixture was stirred at –10 °C for 1 h and then

{1R,3S,4S-4-[(Tetrahydro-2H-pyran-2-yloxy)methyl]spiro[2.2]-

pentan-1-yl}methanol [(1R,3S,4S)-21]: Protected diol (1R,3S,4S)-21

(3.34 g, 93 %) was obtained from protected acid (1R,3S,4S)-20

(3.6 g, 15.91 mmol) and LiAlH₄(1.07 g, 28.2 mmol) according to

1

GP6 as an oil. H NMR (250 MHz, CDCl₃): δ = 0.63–0.68 (m, 2

H, cPr-H), 0.73–0.85 (m, 4 H, cPr-H), 0.97–1.02 (m, 2 H, cPr-H), at ambient temperature for an additional 4 h, the solvent was re-

1.36–1.80 (m, 16 H, cPr-H, THP), 2.34 (br.s, 2 H, OH), 3.17 (dd, moved on a rotary evaporator, and the residue was extracted with

J = 8.0, 10.0 Hz, 1 H, CH₂O), 3.40–3.66 (m, 8 H), 3.77–3.84 (m, 3 pentane (5ϫ 100 mL). The combined extracts were filtered through

H), 4.52–4.35 (m, 1 H), 4.59–4.67 (m, 1 H) ppm. ¹³C NMR

(62.9 MHz, CDCl₃): δ = 6.88 and 6.97 (CH₂), 10.4 (CH₂), 14.4 and

a 3-cm pad of silica gel and evaporated under reduced pressure to

give an essentially pure product as a colorless oil, which was used

14.5 (CH), 17.2 and 17.3 (C), 18.3 and 18.4 (CH₂), 19.0 and 19.4 without further purification.

(CH), 25.27 and 25.31 (CH₂), 30.4 and 30.5 (CH₂), 61.7 and 62.2

(1R,3R,4S)-1-Bromo-4-(bromomethyl)spiro[2.2]pentane [(1R,3R,4S)-

(CH₂), 64.05 and 64.1 (CH₂), 71.1 and 71.4 (CH₂), 98.2 and 98.8

(CH) ppm.

25]: The dibromide (1R,3R,4S)-25 (4.41 g, 91%) was obtained from

bromo alcohol (1S,3R,4R)-13 (3.58 g, 20.22 mmol), PPh₃(5.57 g,

21.23 mmol), Br₂(3.39 g, 1.09 mL, 21.23 mmol) and pyridine

(1.60 g, 20.22 mmol) according to GP8. ¹H NMR (250 MHz,

{1R,3S,4R-4-[(Tetrahydro-2H-pyran-2-yloxy)methyl]spiro[2.2]-

pentan-1-yl}methanol [(1R,3S,4R)-21]: Protected diol (1R,3S,4R)-21

Eur. J. Org. Chem. 2012, 1530–1545

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1539

A. de Meijere et al.

FULL PAPER

CDCl₃): δ = 1.04 (t, J = 5.0 Hz, 1 H, cPr-H), 1.38–1.50 (m, 3 H, 24.1 (CH) ppm. (1R,3R,4R,5R)-32: [α]²_D⁵= +56.6 (c = 1.990,

cPr-H), 1.65–1.81 (m, 1 H, cPr-H), 3.31 (dd, J = 3.6, 6.9 Hz, 1 H,

CHBr), 3.35 (dd, J = 7.1, 10.1 Hz, 1 H, CH₂Br), 3.50 (dd, J = 8.0,

CHCl₃). ¹H NMR (250 MHz, CDCl₃): δ = 1.48–1.53 (m, 4 H, cPr-

H), 1.84 (dd, J = 3.7, 6.2 Hz, 2 H, cPr-H), 3.51 (dd, J = 3.7, 7.1 Hz,

10.1 Hz, 1 H, CH₂Br) ppm. ¹³C NMR (62.9 MHz, CDCl₃): δ = 2 H, cPr-H) ppm. ¹³C NMR (62.9 MHz, CDCl₃): δ = 12.8 (2 CH₂),

13.3 (CH₂), 17.0 (CH₂), 20.9 (CH), 22.3 (CH), 24.6 (C), 36.4 (2 15.0 (CH₂), 20.1 (2 C), 23.6 (2 CH) ppm.

CH₂) ppm.

(1R,3R,4S)-

and

(1S,3R,4S)-1,4-Dibromospiro[2.2]pentane

(1R,3R,4S,5R)-1-Bromo-5-(bromomethyl)dispiro[2.0.2.1]pentane

[(1R,3R,4S,5R)-28]: The dibromide (1R,3R,4S,5R)-28 (551 mg,

83%) was obtained from bromo alcohol (1R,3S,4R,5R)-15

[(1R,3R,4S)-31 and (1S,3R,4S)-31]: Column chromatography [300 g

of flash silica gel, eluent pentane/Et₂O (1:0) to 5:2, GC-monitoring]

of the residue obtained from bromo acid (1S,3R,4S)-18 (2.00 g,

(508 mg, 2.625 mmol), PPh₃(689 mg, 2.625 mmol), Br₂(420 mg, 10.47 mmol) DCC (4.32 g, 20.94 mmol), DMAP (1.28 g,

0.135 mL, 2.625 mmol) and pyridine (198 mg, 2.625 mmol) accord-

ing to GP8. H NMR (250 MHz, CDCl₃): δ = 0.88 (t, J = 4.7 Hz,

1 H, cPr-H), 1.16–1.19 (m, 2 H, cPr-H), 1.26 (d, J = 4.2 Hz, 1 H,

10.47 mmol), and NOSP (2.66 g, 20.94 mmol) in BrCCl₃(50 mL)

according to GP9 afforded 1:1.4 mixture of dibromides

(1R,3R,4S)-31, (1S,3R,4S)-31 (1.62 g, 68%). HPLC-separation of

1

a

cPr-H), 1.56–1.61 (m, 2 H, cPr-H), 2.14–2.25 (m, 1 H, cPr-H), 3.47 this mixture gave (1R,3R,4S)-31 (420 mg, 18%) and (1S,3R,4S)-31

(d, J = 7.6 Hz, 2 H, CH₂Br), 3.49–3.53 (m, 1 H, CHBr) ppm. ¹³C (608 mg, 26%). (1R,3R,4S)-31: colorless oil, [α]²_D⁵= +166.9 (c =

1

NMR (62.9 MHz, CDCl₃): δ = 11.4 (CH₂), 13.6 (CH₂), 15.9 (CH₂),

1.240, CHCl₃). H NMR (250 MHz, CDCl₃): δ = 1.36–1.37 (m, 1

H, cPr-H), 1.51–1.54 (m, 1 H, cPr-H), 1.68–1.70 (m, 1 H, cPr-H),

1.80–1.82 (m, 1 H, cPr-H), 3.30–3.32 (m, 1 H, cPr-H), 3.44–3.46

(m, 1 H, cPr-H) ppm. ¹³C NMR (62.9 MHz, CDCl₃): δ = 17.6

(CH₂), 19.4 (CH₂), 23.5 (C), 24.14 (CH), 24.19 (CH) ppm. HRMS:

calcd. for C₅H₆Br₂[M]: 223.8836, found 223.8836. Compound

(1S,3R,4S)-31: colorless solid, m.p. 49 °C, [α]²_D⁵= +218.2 (c = 1.320,

CHCl₃). ¹H NMR (250 MHz, CDCl₃): δ = 1.38–1.43 (m, 2 H, cPr-

16.5 (CH), 19.0 (C), 24.7 (CH), 24.8 (C), 37.4 (CH₂) ppm.

(1R,3S,4S)1,4-Bis(bromomethyl)spiro[2.2]pentane [(1R,3S,4S)-23]:

The dibromide (1R,3R,4S,5R)-28 (984 mg, 65%) was obtained

from diol (1R,3S,4S)-22 (769 mg, 6.0 mmol), PPh₃(3.305 g,

12.6 mmol), Br₂(2.014 g, 1.064 mL, 12.6 mmol) and pyridine

(950 mg, 12 mmol) according to GP8, [α]²_D⁵= –24.6 (c = 1.220,

1

CHCl₃). H NMR (250 MHz, CDCl₃): δ = 0.80 (t, J = 4.6 Hz, 1

H), 1.60–1.66 (m, 2 H, cPr-H), 3.40–3.46 (m, 2 H, cPr-H) ppm. ¹³

C

H, cPr-H), 1.00 (t, J = 4.6 Hz, 1 H, cPr-H), 1.09 (dd, J = 4.7,

7.5 Hz, 1 H, cPr-H), 1.26 (dd, J = 4.8, 8.0 Hz, 1 H, cPr-H), 1.66–

1.77 (m, 1 H, cPr-H), 1.80–1.93 (m, 1 H, cPr-H), 3.12 (t, J = 9.9 Hz,

NMR (62.9 MHz, CDCl₃): δ = 17.2 (2 CH₂), 23.2 (2 CH), 23.8 (C).

HRMS: calcd. for C₅H₆Br₂[M]: 223.8836, found 223.8836.

1 H, CH₂Br), 3.34 (dd, J = 8.7, 9.7 Hz, 1 H, CH₂Br), 3.60 (dd, J (1R,3S,4S)-

and

(1S,3S,4S)-1,4-Dibromospiro[2.2]pentane

= 6.5, 9.9 Hz, 1 H, CH₂Br), 3.75 (dd, J = 5.4, 9.8 Hz, 1 H,

[(1R,3S,4S)-31 and (1S,3S,4S)-31]: Column chromatography (300 g

of flash silica gel, eluent pentane, GC monitoring) of the residue

CH₂Br) ppm. ¹³C NMR (62.9 MHz, CDCl₃): δ = 11.3 (CH₂), 15.0

(CH₂), 16.8 (CH), 20.0 (CH), 25.2 (C), 37.4 (CH₂), 38.2 obtained from bromo acid (1R,3S,4S)-18 (4.60 g, 24.08 mmol),

(CH₂) ppm.

DCC (11.27 g, 54.6 mmol), DMAP (4.41 g, 36.1 mmol), and NOSP

(7.22 g, 56.8 mmol) in BrCCl₃(120 mL) according to GP9 afforded

dibromides (1R,3S,4S)-31 (2.66 g, 49%) and (1S,3S,4S)-31 (1.10 g,

19%) as colorless oils. (1R,3S,4S)-31: [α]²_D⁵= –161.1 (c = 1.350,

CHCl₃). ¹H NMR (250 MHz, CDCl₃): δ = 1.48–1.51 (m, 2 H, cPr-

General Procedure for the Decarboxylative Bromination of Bromo

Acids (1S,3R,4R,5R)-17, (1S,3R,4S)-18 and (1R,3S,4S)-18. (GP9):

A solution of the respective bromo acid (24 mmol), dicyclohex-

ylcarbodiimide (DCC) (55 mmol), 4-dimethylaminopyridine

(DMAP) (36 mmol), and 2-sulfanylpyridine N-oxide (NOSP)

(57 mmol) in bromotrichloromethane (120 mL) was stirred under

an atmosphere of nitrogen at ambient temperature for 5 h in the

dark. The reaction mixture was then cooled to 0 °C and irradiated

employing a 500 W tungsten lamp at the same temperature for

1.5 h. The resulting mixture was diluted with pentane (300 mL) and

filtered through a 3-cm pad of silica gel. The silica gel was washed

with pentane (50 mL), and the combined solutions were concen-

trated under reduced pressure. If not otherwise specified, the prod-

ucts were isolated by column chromatography on flash silica gel

with GC monitoring.

H), 1.57–1.63 (m, 2 H, cPr-H), 3.50–3.56 (m, 2 H, cPr-H) ppm. ¹³

C

NMR (62.9 MHz, CDCl₃): δ = 17.9 (2 CH₂), 19.1 (2 C), 22.9 (2

CH) ppm. HRMS (M⁺) m/z calcd. for C₅H₆Br₂223.8836, found

223.8836. (1S,3S,4S)-31: [α]²_D⁵= +358.5 (c = 1.330, CHCl₃). ¹H

NMR (250 MHz, CDCl₃): δ = 1.36–1.37 (m, 1 H, cPr-H), 1.51–

1.54 (m, 1 H, cPr-H), 1.68–1.70 (m, 1 H, cPr-H), 1.80–1.82 (m, 1

H, cPr-H), 3.30–3.32 (m, 1 H, cPr-H), 3.44–3.46 (m, 1 H, cPr-

H) ppm. ¹³C NMR (62.9 MHz, CDCl₃): δ = 17.6 (CH₂), 19.4

(CH₂), 23.5 (C), 24.14 (CH), 24.19 (CH) ppm. HRMS: calcd. for

C₅H₆Br₂[M]: 223.8836, found 223.8836.

General Procedure for the Phosphanylation of Dibromides

(1R,3S,4S)-23, (1R,3R,4S)-25 and (1R,3R,4S,5R)-28 (GP10): A

solution of nBuLi in hexanes (2.5 mmol) was added dropwise to a

solution of diphenylphosphane (2.6 mmol) in anhydrous THF

(6 mL) at 0 °C. The orange solution was stirred at the same tem-

perature for an additional 0.5 h, then a solution of the respective

dibromide (1.0 mmol for 23 or 2.0 mmol for 25, 28) in THF (2 mL)

was added dropwise at 0 °C. The reaction mixture was stirred at

the same temperature for an additional 0.5 h, before a solution of

borane·THF complex in THF (2.9 mmol) was added at 0 °C. The

reaction mixture was stirred at the same temperature for an ad-

ditional 0.5 h, the reaction was quenched with MeOH (0.2 mL).

After concentration of the reaction mixture under reduced pres-

sure, the residue was purified by column chromatography.

(1S,3R,4R,5R)- and (1R,3R,4R,5R)-1,5-Dibromodispiro[2.0.2.1]hex-

ane [(1S,3R,4R,5R)-32 and (1R,3R,4R,5R)-32]: Repeated column

chromatography [300 g of flash silica gel each, eluent pentane/Et₂O

(2:1), GC monitoring] of the residue obtained from bromo acid

(1S,3R,4R,5R)-17 (4.954 g, 22.82), DCC (10.68 g, 51.76 mmol),

DMAP (4.179 g, 34.21 mmol), and NOSP (6.84 g, 53.8 mmol) in

BrCCl₃(120 mL) according to GP9 afforded dibromides

(1S,3R,4R,5R)-32 (2.49 g, 43%), (1R,3R,4R,5R)-32 (1.81 g, 31%),

and a ca. 1:1 mixture (1.33 g, 23%) of both as colorless oils.

1

(1S,3R,4R,5R)-32: H NMR (250 MHz, CDCl₃): δ = 1.19 (dd, J =

3.6, 6.2 Hz, 1 H, cPr-H), 1.27 (dd, J = 3.8, 6.2 Hz, 1 H, cPr-H),

1.44 (d, J = 4.5 Hz, 1 H, cPr-H), 1.60 (dd, J = 0.6, 4.7 Hz, 1 H,

cPr-H), 1.69 (t, J = 6.6 Hz, 1 H, cPr-H), 2.02 (t, J = 6.6 Hz, 1 H,

cPr-H), 3.20 (ddd, J = 1.1, 3.8, 4.8 Hz, 1 H, cPr-H), 3.44 (dd, J =

(1R,3S,4S)-1,4-Bis[methyl(diphenyl)phosphanylborane]spiro[2.2]-

3.7, 7.1 Hz, 1 H, cPr-H) ppm. ¹³C NMR (62.9 MHz, CDCl₃): δ = pentane [(1R,3S,4S)-24·(BH₃)₂]: Column chromatography (80 g of

13.9 (CH₂), 14.9 (CH₂), 15.9 (CH₂), 21.5 (C), 21.8 (CH), 23.9 (C), silica gel, eluent pentane/Et₂O, 3:1) of the residue obtained from

1540

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Eur. J. Org. Chem. 2012, 1530–1545

New Chiral Triangulane-Based Diphosphane Ligands

dibromide (1R,3S,4S)-23 (933 mg, 3.67 mmol), nBuLi (9.0 mmol,

without further purification. ¹H NMR (300 MHz, CDCl₃): δ = 0.64

3.38 mL of a 2.86 m solution), Ph₂PH (1.779 g, 1.66 mL, (t, J = 5.01 Hz, 1 H, cPr-H), 0.94 (dd, J = 4.8, 8.1 Hz, 1 H, cPr-

9.56 mmol) and BH₃·THF (10.6 mmol, 10.6 mL of a 1 m solution)

according to GP10 afforded the ligand (1R,3S,4S)-24·(BH₃)₂

(1.437 g, 80%) as a glass, [α]²_D⁵= –39.3 (c = 0.550, CHCl₃). ¹H

H), 0.99–1.06 (m, 3 H, cPr-H), 1.45 (t, J = 6.4 Hz, 1 H, cPr-H),

1.76–1.86 (m, 1 H, cPr-H), 2.23–2.46 (m, 2 H, CH₂P), 3.38 (dd, J

= 3.5, 6.9 Hz, 1 H, CHBr), 7.44–7.78 (m, 10 H, Ar-H) ppm. ¹³C

NMR (600 MHz, CDCl₃): δ = 0.38 (t, J = 4.3 Hz, 1 H, cPr-H), NMR (62.9 MHz, CDCl₃): δ = 8.78 (CH), 12.5 (CH₂), 12.6 (d, ¹J_CP

3

0.51 (t, J = 4.6 Hz, 1 H, cPr-H), 0.77 (dd, J = 4.3, 7.9 Hz, 1 H,

cPr-H), 0.85 (dd, J = 4.6, 7.9 Hz, 1 H, cPr-H), 0.87–0.94 (m, 1 H,

cPr-H), 1.28–1.34 (m, 1 H, cPr-H), 2.10–2.15 (m, 1 H, cPr-H),

= 5.6 Hz, CH₂), 15.7 (CH₂), 19.4 (C), 22.9 (d, J_CP= 7.3 Hz, C),

1

25.1 (CH), 29.8 (d, J_CP= 35.8 Hz, CH₂), 128.6–133.0 (CH and C

1

of aryls) ppm. ³¹P NMR (121 MHz, CDCl₃): δ = 16.3 (br. d, J_BP

2.19–2.23 (m, 2 H, cPr-H), 2.33–2.39 (m, 1 H, cPr-H), 7.31–7.69 = 67 Hz) ppm.

(m, 20 H, Ar-H) ppm. ¹³C NMR (150.8 MHz, CDCl₃): δ = 10.2

General Procedure for the Bromine-Lithium Exchange with Subse-

(d, J_CP= 2.0 Hz, CH₂), 11.8 (d, J_CP= 7.7 Hz, CH₂), 13.3 (d, J_CP

= 1.5 Hz, CH), 14.3 (d, J_CP= 7.7 Hz, CH₂), 22.5 (dd, J_CP= 6.6,

quent Phosphanylation of Bromides (1S,3R,4R)-26·BH₃and

(1R,3S,4R,5R)-29·BH₃(GP11): A solution of tBuLi in pentane

(2.1 mmol) was added dropwise to a solution of the respective

bromide (0.96 mmol) in anhydrous Et₂O (14 mL) at –78 °C. After

stirring at this temperature for an additional 20 min, Ph₂PCl

(1.2 mmol) was added from a syringe, the reaction mixture was

warmed up to ambient temperature over a period of 1 h. A solution

of borane·THF complex in THF (2.5 mmol) was added at 0 °C, the

reaction mixture was stirred at this temperature for an additional

1 h, and the reaction was then quenched with MeOH (1 mL). After

concentration of the reaction mixture under reduced pressure, the

residue was purified by flash column chromatography.

1

7.4 Hz, C), 28.6 (d, ¹J_CP= 36.2 Hz, CH₂), 29.8 (d, J_CP= 36.0 Hz,

CH₂), 128.5–132.4 (CH and C of aryls) ppm. ³¹P NMR (121 MHz,

CDCl₃): δ = 15.9 (br. s) ppm. HRMS (–ESI): calcd. for

C₃₁H₃₆B₂NaP₂[M + Na]⁺: 515.2343; found 515.2376.

(1S,3R,4R)-4-[Bromospiro[2.2]pent-1-yl]methyl(diphenylphosphanyl)-

borane [(1S,3R,4R)-26·BH₃]: Column chromatography (50 g of sil-

ica gel, eluent pentane/Et₂O, 1:0 to 12.5:1) of the residue obtained

from dibromide (1R,3R,4S)-25 (480 mg, 2 mmol), nBuLi

(2.60 mmol, 1.0 mL of a 2.59 m solution), Ph₂PH (428 mg,

2.3 mmol, 0.40 mL) and BH₃·THF (2.44 mmol, 2.44 mL of a 1 m

solution) according to GP10 afforded the (1S,3R,4R)-26·BH₃

(400 mg, 58%) as a solid along with {(1S,3R,4R)-4-bromospiro-

[2.2]pent-1-yl}methyldiphenylphosphane [(1S,3R,4R)-26] (70 mg,

10%) as an oil. (1S,3R,4R)-26·BH₃: M.p. 84–85 °C (hexane/Et₂O),

[(1R,3R,4S)-4-(Diphenylphosphanyl)methylspiro[2.2]pentan-1-yl]di-

phenylphosphane Bis-borane Complex [(1R,3R,4S)-27·(BH₃)₂]: Col-

umn chromatography (50 g of silica gel, eluent pentane/Et₂O, 4:1)

of the residue obtained from bromide (1S,3R,4R)-26·BH₃(334 mg,

0.958 mmol), tBuLi (2.1 mmol, 1.43 mL of a 1.50 m solution),

Ph₂PCl (268 mg, 1.22 mmol) and BH₃·THF (2.4 mmol, 2.4 mL of

a 1 m solution) according to GP11 afforded 346 mg of a waxy oil,

recrystallization of which from MeOH furnished (1R,3R,4S)-

1

[α]²_D⁵= +50.0 (c = 1.100, CHCl₃). H NMR (250 MHz, CDCl₃): δ

= 0.79 (t, J = 5.1 Hz, 1 H, cPr-H), 1.11 (dd, J = 3.4, 5.8 Hz, 1 H,

cPr-H), 1.25 (dd, J = 5.0, 8.0 Hz, 1 H, cPr-H), 1.37–1.42 (m, 2 H,

cPr-H), 1.87–2.01 (m, 1 H, CH₂P), 2.61–2.72 (m, 1 H, CH₂P), 3.22–

3.28 (m, 1 H, CH₂Br), 7.41–7.50 (m, 6 H, Ar-H), 7.68–7.75 (m, 4

27·(BH₃)₂(302 mg, 66%) as a solid, m.p. 129–130 °C, [α]²_D⁵

=

2

H, Ar-H) ppm. ¹³C NMR (62.9 MHz, CDCl₃): δ = 13.8 (d, J_CP

=

+111.5 (c = 1.040, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.85

(dd, J = 4.8, 9.6 Hz, 1 H, cPr-H), 1.06 (dd, J = 5.7, 7.8 Hz, 1 H,

cPr-H), 1.22–1.25 (m, 1 H, cPr-H), 1.41–1.45 (m, 1 H, cPr-H),

1.58–1.68 (m, 2 H, CHP, cPr-H), 1.89–1.92 (m, 1 H, CHP), 2.99–

3.05 (m, 1 H, CHP), 7.38–7.42 (m, 2 H, Ar-H), 7.44–7.60 (m, 12

H, Ar-H), 7.66–7.71 (m, 4 H, Ar-H), 7.80–7.86 (m, 2 H, Ar-

H) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 9.1 (CH₂), 11.6 (d,

²J_CP= 4.4 Hz, CH, cPr-C), 12.3 (d, ¹J_CP= 58 Hz, CH), 12.8 (CH₂),

3

1.4 Hz, CH), 14.3 (CH₂), 16.5 (d, J_CP= 3.2 Hz, CH₂), 22.4 (d,

³J_CP= 13.6 Hz, C), 23.6 (CH), 29.1 (d, ¹J_CP= 36.2 Hz, CH₂), 128.6

3

1

(d, J_CP= 10.0 Hz, CH), 128.7 (d, J_CP= 55.0 Hz, C), 128.7 (d,

³J_CP= 10.0 Hz, CH), 129.6 (d, J_CP= 55.0 Hz, C), 131.1 (d, J_CP

1

4

2

= 2.5 Hz, CH), 131.2 (d, J_CP= 2.5 Hz, CH), 132.1 (d, J_CP

=

18.0 Hz, CH), 132.3 (d, J_CP= 18.0 Hz, CH) ppm. ³¹P NMR

2

1

(121 MHz, CDCl₃): δ = 16.3 (br. d, J_{B P}= 67 Hz) ppm.

C₁₈H₂₁BBrP (359.05): calcd. C 60.21, H 5.90; found C 60.43, H

3

2

1

19.7 (dd, J_CP= 2.6, J_CP= 17.0 Hz, C), 28.3 (d, J_CP= 37.0 Hz,

CH₂), 128.02, 128.46, 128.58, 128.63, 128.66, 128.71, 128.74,

129.53, 129.99, 130.86, 130.88, 130.91, 131.04, 131.06, 131.11,

131.13, 131.33, 131.79, 131.81, 131.86, 131.88, 131.91,

131.99,132.56, 132.63 (CH and C of aryls) ppm. ³¹P NMR

5.98. The absolute configuration of (1S,3R,4R)-26·BH₃was estab-

1

lished by an X-ray crystal structure analysis.^[16](1S,3R,4R)-26: H

NMR (250 MHz, CDCl₃): δ = 0.82–0.85 (m, 1 H, cPr-H), 1.24–

1.34 (m, 3 H, cPr-H), 1.40–1.45 (m, 1 H, cPr-H), 2.03–2.12 (m, 1

H, CH₂P), 2.21–2.29 (m, 1 H, CH₂P), 3.29–3.33 (m, 1 H, CH₂Br),

7.31–7.36 (m, 6 H, Ar-H), 7.45–7.52 (m, 4 H, Ar-H ppm. ¹³C NMR

1

(121 MHz, CDCl₃): δ = 16.1 (br. d, J_BP= 52 Hz), 23.2 (br. d, ¹J_BP

2

= 40 Hz) ppm. HRMS (–DCI): m/z calcd. for C₃₀H₃₈B₂NP₂[M +

NH₄]⁺494.27327; found 494.27328. The absolute configuration of

(1R,3R,4S)-27·(BH₃)₂was established by X-ray crystal structure

analysis.^[16]

(62.9 MHz, CDCl₃): δ = 14.2 (CH₂), 16.9 (d, J_CP= 17 Hz, CH),

3

16.7 (d, J_CP= 8.2 Hz, CH₂), 23.4 (d, J_CP= 11.0 Hz, C, cPr-C),

1

24.3 (CH), 31.6 (d, J_CP= 12.4 Hz, CH₂), 128.2, 128.3, 128.34,

128.40, 128.44, 128.58 (m, all-CH), 132.6 (d, J_CP= 19 Hz, CH),

133.0 (d, J_CP= 19 Hz, CH), 138.5 (d, J_CP= 14 Hz, C), 138.6 (d,

¹J_CP= 14 Hz, C) ppm. ³¹P NMR (121 MHz, CDCl₃): δ =

–18.7 ppm. C₁₈H₁₈BrP (345.21): calcd. C 62.63, H 5.26; found C

62.78, H 5.19.

2

1

[(1R,3R,4S,5R)-5-(Diphenylphosphanyl)methyldispiro[2.0.2.1]hept-

an-1-yl]diphenylphosphane Bis-borane Complex [(1R,3R,4S,5R)-

30·(BH₃)₂]: Column chromatography (50 g of silica gel, eluent pent-

ane/Et₂O, 4:1) of the residue obtained from bromide (1R,3S,4R,5R)-

29·BH₃(440 mg, 1.143 mmol), tBuLi (2.55 mmol, 1.56 mL of a

1.637 m solution), Ph₂PCl (515 mg, 2.33 mmol) and BH₃·THF

(3.0 mmol, 3.0 mL of a 1 m solution) according to GP11 afforded

(1R,3S,4R,5R)-(5-Bromodispiro[2.0.2.1]hept-1-yl)methyl(diphenyl-

phosphanyl)borane [(1R,3S,4R,5R)-29·BH₃]: Column chromatog-

raphy (60 g of silica gel, eluent pentane/Et₂O, 1:0 to 12.5:1) of the

residue obtained from (1R,3R,4S,5R)-28 (0.537 mg, 2.02 mmol), a waxy oil, recrystallization of which from MeOH furnished

nBuLi (2.47 mmol, 1.0 mL of a 2.509 m solution), Ph₂PH (489 mg, (1R,3R,4S,5R)-30·(BH₃)₂(180 mg, 31%) as a solid, m.p. 147 °C,

0.46 mL, 2.63 mmol) and BH₃·THF (2.9 mmol, 2.9 mL of a 1 m [α]²_D⁵= –37.0 (c = 1.170, CHCl₃). H NMR (600 MHz, CDCl₃): δ

1

solution) according to GP10 afforded (1R,3S,4R,5R)-29·BH₃

(469 mg, 60%) as an oil, which was used in the subsequent step

= 0.38 (t, J = 4.9 Hz, 1 H, cPr-H), 0.89 (dd, J = 5.0, 7.8 Hz, 1 H,

cPr-H), 1.06–1.11 (m, 2 H, cPr-H), 1.19 (d, J = 4.1 Hz, 1 H, cPr-

Eur. J. Org. Chem. 2012, 1530–1545

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1541

A. de Meijere et al.

FULL PAPER

H), 1.43–1.46 (m, 1 H, cPr-H), 1.54–1.62 (m, 2 H, cPr-H), 1.96–

1.98 (m, 1 H, CHP), 2.04–2.08 (m, 1 H, CHP), 7.32–7.59 (m, 20

7.63 (m, 20 H, Ar-H) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ =

10.5 (dd, J_CP= 4.0, 54.0 Hz, CH), 10.7 (CH₂), 12.2 (dd, J_CP

=

H, Ar-H) ppm. ¹³C NMR (150.8 MHz, CDCl₃): δ = 10.0 (d, J_CP

=

1.2 Hz, CH), 55.0 Hz, 12.3 (d, J_CP= 3.0 Hz, CH₂), 20.3 (dd, J_CP

1.9 Hz, CH₂), 10.9 (CH₂), 12.3 (d, J_CP= 2.5 Hz, CH₂), 13.0 (d, J_CP

= 1.1 Hz, CH), 13.7 (¹J_CP= 58.0 Hz, CH), 19.4 (dd, J_CP= 6.7,

15.3 Hz, C),19.9 (dd, J_CP= 1.6, 3.7 Hz, C), 29.0 (d, ¹J_CP= 35.0 Hz,

CH₂), 128.50, 128.54, 128.56, 128.60, 128.73, 128.79, 128.92,

129.20, 129.56, 130.55, 130.72, 130.73, 130.90, 130.91, 130.92,

130.98, 130.99, 131.65, 131.71, 131.95, 132.01, 132.09, 132.24,

132.30, 132.47, 132.53 (CH and C of aryls) ppm. ³¹P NMR

= 1.2, 4.1 Hz, C), 128.5–133.4 (CH and C of aryls) ppm. ³¹P NMR

1

(121 MHz, CDCl₃): δ = 21.0 (br. d, J_BP= 51.0 Hz), 22.8 (br. d,

¹J_BP= 54.0 Hz) ppm. HRMS (–ESI): calcd. for C₂₉H₃₂B₂NaP₂[M

+ Na]⁺485.21302; found 485.21317.

Experiment 2: Column chromatography (150 g of silica gel, eluent

pentane/Et₂O, 10:1 to 2:1) of the residue obtained from dibromide

(1R,3S,4S)-31 (226 mg, 1.0 mmol), tBuLi (15.0 mmol, 8.5 mL of a

1.78 m solution), Ph₂PCl (3.31 g, 2.639 mL, 15 mmol) and

BH₃·THF (17 mmol, 17.0 mL of a 1 m solution) according to GP12

afforded (1R,3S,4S)-35·(BH₃)₂(170 mg, 37%) as a glass and tert-

butyldiphenylphosphane (33) (3.56 g, 93%).

1

(121 MHz, CDCl₃): δ = 16.8 (br. d, J_BP= 51 Hz), 21.4 (br. d, ¹J_BP

= 43 Hz) ppm. C₃₂H₃₆B₂P₂(504.20): calcd. C 76.23, H 7.20; found

C 76.45, H 7.12. The absolute configuration of the product was

established by X-ray crystal structure analysis.^[16]

Attempted Preparation of (1S,3R,4S)-1,4-Bis(diphenylphosphanyl)-

spiropentane Bis-borane Complex [(1S,3R,4S)-35·(BH₃)₂]: Column

chromatography (100 g of silica gel, eluent pentane/EtOAc, 5:1) of

the residue obtained from dibromide (1S,3R,4S)-31 (580 mg,

2.57 mmol), tBuLi (10.15 mmol, 5.70 mL of a 1.78 m solution),

Ph₂PCl (1.273 g, 1.04 mL, 5.77 mmol) and BH₃·THF (13.5 mmol,

13.5 mL of a 1 m solution) according to GP11 afforded a waxy oil

which crystallized to give tert-butyldiphenylphosphane (33) (1.46 g,

99%) as a single product.

(1S,3S,4S)-1,4-Bis(diphenylphosphanyl)spiropentane

Bis-borane

Complex [(1S,3S,4S)-35·(BH₃)₂]: Column chromatography (150 g

of silica gel, eluent pentane/Et₂O, 10:1 to 2:1) of the residue ob-

tained from dibromide (1S,3S,4S)-31 (226 mg, 1.0 mmol), tBuLi

(15.0 mmol, 8.5 mL of

a 1.78 m solution), Ph₂PCl (3.31 g,

2.639 mL, 15 mmol) and BH₃·THF (17 mmol, 17.0 mL of a 1 m

solution) according to GP12 afforded (1S,3S,4S)-35·(BH₃)₂

(370 mg, 80%) as a solid, m.p. 164–165 °C (hexane/diethyl ether),

[α]²_D⁵= +47.5 (c = 0.650, CHCl₃). H NMR (500 MHz, CDCl₃): δ

1

= 1.37–1.46 (m, 2 H), 1.76–1.86 (m, 2 H), 2.31–2.38 (m, 2 H), 7.35–

7.61 (m, 20 H) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 12.3 (2

CH₂), 15.0 (J_CP= 53.4 Hz, CH), 15.1 (d, J_CP= 53.4 Hz, CH), 22.4

(t, J_CP= 3.9 Hz, C), 127.9–134.2 (CH and C of aryls) ppm. ³¹P

NMR (202 MHz, CDCl₃): δ = 21.9 (br. s) ppm. HRMS (–ESI):

calcd. for C₂₉H₃₂B₂NaP₂[M + Na]⁺485.21302; found 485.21332.

The absolute configuration of the product was established by X-

ray crystal structure analysis.^[16]

General Procedure for the Bromine-Lithium Exchange with Subse-

quent Phosphanylation of Dibromides (1R,3S,4S)-31, (1S,3S,4S)-31

and (1R,3R,4R,5R)-32 (GP12): A solution of tBuLi in pentane

(60 mmol) was added dropwise over a period of 10 min to a stirred

solution of the respective dibromide (4.0 mmol) in anhydrous Et₂O

(200 mL) at –110 °C. After stirring at this temperature for an ad-

ditional 1 h, Ph₂PCl (60 mmol) was added from a syringe, the reac-

tion mixture was warmed up to ambient temperature over a period

of 3 h. A solution of borane·THF complex in THF (68 mmol) was

added at 0 °C, the reaction mixture was stirred at this temperature

for an additional 1 h, and the reaction was then quenched with

MeOH (6 mL). After concentration of the reaction mixture under

reduced pressure, the residue was purified by flash column

chromatography.

(1R,3R,4S)-1,4-Bis(diphenylphosphanyl)spiropentane

Bis-borane

Complex [(1R,3R,4S)-35·(BH₃)₂]: Column chromatography (75 g of

silica gel, eluent pentane/Et₂O, 3:1 to 2:1) of the residue obtained

from dibromide (1R,3R,4S)-31 (349 mg, 1.55 mmol), tBuLi

(23.2 mmol, 14.2 mL of

a 1.64 m solution), Ph₂PCl (5.12 g,

4.17 mL, 23.2 mmol) and BH₃·THF (26.3 mmol, 26.3 mL of a 1 m

solution) according to GP12 afforded (1R,3R,4S)-35·(BH₃)₂

(1R,3S,4S)-1,4-Bis(diphenylphosphanyl)spiropentane

Bis-borane

1

(231 mg, 32%) as a glass, [α]²_D⁵= +61.9 (c = 1.130, CHCl₃). Its H

Complex [(1R,3S,4S)-35·(BH₃)₂]: Experiment 1: Column

chromatography (25 g of silica gel, eluent pentane/EtOAc, 100:1)

of the residue obtained from dibromide (1R,3S,4S)-31 (113 mg,

and ¹³C NMR spectra were identical with those of its enantiomer

(1R,3S,4S)-35·(BH₃)₂.

0.5 mmol), tBuLi (3.0 mmol, 1.68 mL of a 1.78 m solution), Ph₂PCl (1R,3R,4R,5R)-1,5-Bis(diphenylphosphanyl)dispiro[2.0.2.1]heptane

(0.662 g, 0.54 mL, 3 mmol) and BH₃·THF (3 mmol, 3.0 mL of a Bis-borane Complex [(1R,3R,4R,5R)-36·(BH₃)₂]: Column

1 m solution) according to GP12 afforded [(1S,3S,4R)-4-bromo-

chromatography (60 g of silica gel, eluent pentane/Et₂O, 3:1 to 2:1,

then CHCl₃/Et₂O, 1:1) of the residue obtained from dibromide

(1R,3R,4R,5R)-32 (1008 mg, 4 mmol), tBuLi (60 mmol, 35.5 mL of

a 1.70 m solution), Ph₂PCl (13.238 g, 60 mmol) and BH₃·THF

spiro[2.2]pentan-1-yl]diphenylphosphane

[(1S,3S,4R)-34·BH₃] (15 mg, 9%) as

bromospiro[2.2]pentan-1-yl]diphenylphosphane–borane complex

borane

a solid, [(1R,3S,4S)-4-

complex

[(1R,3S,4S)-34·BH₃] (58 mg, 34%) as a waxy oil, tert-butyldiphen- (68.4 mmol, 68.4 mL of a 1 m solution) according to GP12 afforded

ylphosphane (33) (320 mg, 42%) and (1R,3S,4S)-35·(BH₃)₂(33 mg,

14%) as a glass. The absolute configuration of (1S,3S,4R)-34·BH₃

was established by X-ray crystal structure analysis.^[16](1R,3S,4S)-

34·BH₃: ¹H NMR (500 MHz, CDCl₃): δ = 1.26–1.32 (m, 1 H),

1.59–1.73 (m, 2 H), 1.85–2.00 (m, 2 H), 3.24–3.31 (m, 1 H), 7.42–

7.81 (m, 10 H, Ar-H) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ =

the product as a solid. Recrystallization from Et₂O/hexane/CH₂Cl₂

furnished (1R,3R,4R,5R)-36·(BH₃)₂(546 mg, 28%) as a solid, m.p.

1

Ͼ 260 °C (decomp.), [α]²_D⁵= +130.0 (c = 0.360, CHCl₃). H NMR

(300 MHz, CDCl₃): δ = 1.21–1.23 (m, 2 H, cPr-H), 1.32–1.43 (m,

2 H, cPr-H), 1.77–1.82 (m, 2 H, cPr-H), 7.31–7.36 (m, 20 H, Ar-

H) ppm. ¹³C NMR (150.8 MHz, CDCl₃): δ = 13.3 (2 CH₂, d, J_CP

13.0 (d, J_CP= 57 Hz, CH), 13.5 (CH₂), 15.8 (d, J_CP= 4.4 Hz, CH₂), = 2.2 Hz), 14.5 (CH₂, t, J_CP= 1.8 Hz), 16.8 (2 CH, d, J_CP

=

21.5 (d, J_CP= 1.1 Hz, CH), 21.6 (d, J_CP= 2.9 Hz, C), 128.3–134.0

53.9 Hz), 20.3 (2 C, t, J_CP= 5.1 Hz), 128.57 (2 CH, d, J_CP

=

(CH and C of aryls) ppm. ³¹P NMR (121 MHz, CDCl₃): δ = 22.5 9.9 Hz), 128.59 (2 CH, d, J_CP= 10.0 Hz), 130.7 (2 CH, d, J_CP

1

(br. d, J_BP

=

67 Hz) ppm. HRMS (–ESI): calcd. for

2.4 Hz), 130.9 (2 CH, d, J_CP= 2.4 Hz), 131.2 (2 C, d, J_CP

C₁₇H₁₉BBrNaP [M

+

Na]⁺366.04293; found 366.04274. 56.8 Hz), 131.7 (2 C, d, J_CP= 56.3 Hz), 132.4 (2 CH, d, J_CP

1

(1R,3S,4S)-35·(BH₃)₂: [α]²_D⁵= –64.1 (c = 0.590, CHCl₃). H NMR

25.8 Hz), 132.5 (2 CH, d, J_CP

=

25.9 Hz) ppm. ³¹P NMR

(500 MHz, CDCl₃): δ = 1.39–1.43 (m, 1 H), 1.57–1.62 (m, 1 H), (202 MHz, CDCl₃): δ = 19.81 (d, J_B-P= 47.2 Hz) ppm. HRMS

1.69–1.72 (m, 1 H), 1.78–1.83 (m, 2 H), 1.92–1.97 (m, 1 H), 7.26–

(–DCI): calcd. for C₃₁H₃₈B₂NP₂[M + NH₄]⁺506.27327; found

1542

www.eurjoc.org

Eur. J. Org. Chem. 2012, 1530–1545

New Chiral Triangulane-Based Diphosphane Ligands

506.27325. The absolute configuration of the product was estab-

lished by X-ray crystal structure analysis.^[16]

(1RS,3SR,4SR)-14, (1R,3S,4S)-18 and (1S,3S,4S)-35·(BH₃)₂] and

on a Bruker SMART CCD 6000 (other compounds) diffractometer

(graphite monochromator, Mo-K_αradiation), equipped with Cryo-

stream (Oxford Cryosystems) low-temperature devices. The struc-

tures were solved by direct methods and refined by full-matrix

least-squares on F². All non-hydrogen atoms were refined aniso-

tropically. The treatment of H atoms varied for the different struc-

tures, but in most cases the H atoms were located in the difference

Fourier map and refined isotropically. Absolute configurations of

all compounds were determined on the basis of X-ray data. The

Crystal Structure Determinations: Suitable crystals of the com-

pounds (1RS,3SR,4SR)-14, (1R,3S,4R,5S)-16, (1S,3R,4R,5R)-17,

(1R,3S,4S)-18,

(1R,3R,4S,5R)-30·(BH₃)₂,

(1S,3R,4R)-26·BH₃,

(1S,3S,4R)-34·BH₃,

(1R,3R,4S)-27·(BH₃)₂,

(1S,3S,4S)-35·

(BH₃)₂and (1R,3R,4R,5R)-36·(BH₃)₂were grown by slowly con-

centrating their diluted solutions. Single-crystal X-ray data were

collected at 120 K on a Bruker Apex Proteum-M [compounds

Table 3. Crystal and data collection parameters for compounds (1RS,3SR,4SR)-14, (1R,3S,4R,5S)-16, (1S,3R,4R,5R)-17, (1R,3S,4S)-18,

(1S,3R,4R)-26·BH₃.

Compound

(1RS,3SR,4SR)-14

(1R,3S,4R,5S)-16

(1S,3R,4R,5R)-17

(1R,3S,4S)-18

(1S,3R,4R)-26·BH₃

Formula

Molecular mass

Crystal system

Space group

a /Å

b /Å

c /Å

α /°

C₁₃H₁₁N₂O₆Br

371.15

monoclinic

P2₁

6.5215(6)

9.5859(9)

11.6880(11)

90

C₁₅H₁₃BrN₂O₆

397.18

orthorhombic

P2₁2₁2₁

5.1468(2)

10.7245(4)

27.9267(10)

90

C₈H₉BrO₂

217.06

monoclinic

P2₁

6.5379(6)

13.1729(12)

19.877(2)

90

C₆H₇BrO₂

191.03

orthorhombic

P2₁2₁2₁

9.8674(8)

10.3923(8)

13.6444(11)

90

C₁₈H₂₁BBrP

359.04

monoclinic

P2₁

6.6401(1)

14.5834(3)

9.0815(2)

90

β /°

101.18(3)

90

716.80(12)

2

90

99.11(3)

90

1690.2(3)

8

90

92.53(1)

90

878.55(3)

2

γ /°

V /Å³

1541.47(10)

4

1399.16(19)

8

Z

F(000)

372

1.720

2.899

800

1.711

2.703

864

1.706

4.810

752

1.814

5.797

368

1.357

2.421

D /gcm^–3

μ /mm^–1

Reflections collected

Reflections independent 2732

4912

24892

4297

18681

7757

15714

3901

11396

4848

R_int

R₁[IՆ2σ(I)]

wR₂(all data)

0.0250

0.0637

0.1847

0.0278

0.0207

0.0511

269

0.0807

0.0690

0.1736

401

0.0430

0.0251

0.0596

219

0.0137

0.0194

0.0517

274

Number of parameters 200

Refined parameters,

GOOF

1.089

1.101

0.996

1.056

0.990

Table 4. Crystal and data collection parameters for compounds (1R,3R,4S)-27·(BH₃)₂, (1R,3R,4S,5R)-30·(BH₃)₂(1R,3S,4S)-34·BH₃,

(1S,3S,4S)-35·(BH₃)₂and (1R,3R,4R,5R)-36·(BH₃)₂.

Compound

(1R,3R,4S)-27· (1R,3R,4S,5R)-30·

(1S,3S,4R)-34·

BH₃

(1S,3S,4S)-35·

(BH₃)₂

(1R,3R,4R,5R)-36·

(BH₃)₂

Formula

Molecular mass

Crystals

Space group

a /Å

b /Å

c /Å

α /°

C₃₀H₃₄B₂P₂

478.135

monoclinic

P2₁

8.4128(2)

8.9431(2)

18.0075(4)

90

91.92(1)

90

1354.06(5)

2

C₃₂H₃₆B₂P₂·0.5 CHCl₃C₁₇H₁₉BBrP

C₂₉H₃₂B₂P₂

464.11

monoclinic

P2₁

9.0345(12)

23.307(4)

25.280(3)

90

97.65(4)

90

5275.7(13)

8

C₃₁H₃₄B₂P₂

490.14

orthorhombic

P2₁2₁2₁

9.0799(1)

14.9560(2)

19.9882(3)

90

583.85

triclinic

P1

345.01

monoclinic

P2₁

6.5786(2)

15.4884(6)

8.5891(3)

90

9.645(1)

9.787(1)

18.021(2)

79.98(3)

77.51(3)

71.22(3)

1562.4(3)

2

β /°

107.45(1)

90

γ /°

V /Å³

834.90(5)

2

2714.38(6)

4

Z

F(000)

508

1.173

0.177

563.7

1.199

0.288

352

1.372

2.545

1968

1.169

0.180

1040

1.199

0.178

D /gcm^–3

μ /mm^–1

Reflections collected

Reflections independent

R_int

R₁[IՆ2σ(I)]

wR₂(all data)

Number of parameters

Refined parameters,

GOOF

17285

7512

0.0286

0.0294

0.0748

443

3849

3847

0.128

0.1441

0.4150

241

9053

4616

0.0196

0.0277

0.0663

257

32514

20538

0.1257

0.0803

0.1594

1189

42699

7908

0.0443

0.0315

0.0808

452

0.991

1.284

1.034

0.914

1.062

Eur. J. Org. Chem. 2012, 1530–1545

www.eurjoc.org

1543

A. de Meijere et al.

FULL PAPER

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parameters of crystal data collections and structure refinements are

presented in Tables 3 and 4.^[16]

Acknowledgments

a) A. de Meijere, A. F. Khlebnikov, S. I. Kozhushkov, D. S. Yu-

fit, O. V. Chetina, J. A. K. Howard, T. Kurahashi, K. Miyaz-

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CCDC-859012 [for (1RS,3SR,4SR)-14], -859013 [for

(1R,3S,4R,5S)-16], -859014 [for (1S,3R,4R,5R)-17], -859015

[for (1R,3S,4S)-18], -859016 [for (1S,3R,4R)-26·BH₃], -859017

[for (1R,3R,4S)-27·(BH₃)₂], -859018 [for (1S,3S,4R)-34·BH₃],

-859019 [for (1S,3S,4S)-35·(BH₃)₂] and -859020 [for

(1R,3R,4R,5R)-36·(BH₃)₂] contain the supplementary crystal-

lographic data for this paper. These data can be obtained free

of charge from The Cambridge Crystallographic Data Centre

via www.ccdc.cam.ac.uk/data_request/cif. The X-ray crystal

structure analyses of the compound (1R,3R,4S,5R)-30 does es-

tablish its relative configuration, but the poor quality of the

crystals of this compound led to inaccurate geometrical param-

eters and unsatisfactorily high R values, which neither permit

to discuss any structural peculiarities of this compound nor

to save the results of these measurements in the Cambridge

Crystallographic Data Centre.

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Received: November 29, 2011

Published Online: January 31, 2011

Eur. J. Org. Chem. 2012, 1530–1545

www.eurjoc.org

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Article Doi

A novel type of chiral triangulane-based diphosphane ligands for transition metals

DOI: 10.1002/ejoc.201101715

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