H-adamantylphosphinates as universal precursors of P-stereogenic compounds

Article abstract of DOI:10.1021/acs.joc.5b00548

A new family of H-adamantylphosphinates as universal precursors of P-stereogenic ligands was obtained in one step from commercial chlorophosphines. Both enantiomers of these air- and moisture-stable intermediates can easily be separated by semipreparative chiral HPLC on a gram scale and individually undergo stereoselective transformations to afford each enantiomer of a set of P-stereogenic compounds such as secondary phosphine oxides and boron-protected monophosphines.

Full text of DOI:10.1021/acs.joc.5b00548

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Article
H-adamantylphosphinates as universal
precursors of P-stereogenic compounds
David Gatineau, Duc Hanh Nguyen, Damien Hérault, Nicolas
Vanthuyne, Julien Leclaire, Laurent Giordano, and Gérard Buono
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00548 • Publication Date (Web): 25 Mar 2015
Downloaded from http://pubs.acs.org on March 30, 2015
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The Journal of Organic Chemistry
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H-adamantylphosphinates as universal precursors of P-stereogenic
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David Gatineau, Duc Hanh Nguyen, Damien Hérault, Nicolas Vanthuyne, Julien Leclaire*†, Lau-
rent Giordano* and Gérard Buono
Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397, Marseille, France
ABSTRACT: A new family of H-adamantylphosphinates as universal precursors of P-stereogenic ligands was obtained in
one step from commercial chlorophosphines. Both enantiomers of these air and moisture stable intermediates can easily
be separated by semi-preparative chiral HPLC in gram scale and individually undergo stereoselective transformations to
afford each enantiomers of a set of P-stereogenic compounds such as secondary phosphine oxides and boron-protected
monophosphines.
INTRODUCTION
Phosphorus donor species undoubtedly represent one of the major classes of transition metal ligands, which have large-
ly contributed to the evolution of catalysis into an indispensable tool in organic synthesis and the industrial production of
chemicals. In contrast to the lighter pictogen element nitrogen, the inversion barrier of tricoordinated phosphorus is
high, allowing for the obtention of P-stereogenic trivalent phosphorus ligands, which may thereby bring the chiral center
in close proximity to the metal in subsequent complexes. While this perspective potentially holds great promises in
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asymmetric catalysis, mastering the substitution pattern on trivalent phosphorus centers represents a major synthetic
challenge. A conventional route to trivalent P-stereogenic architectures consists in stereoselectively producing pentava-
lent P-stereogenic precursors. While the reactive center displays a tetrahedral geometry reminiscent of carbon, substitu-
tion reactions generally do not follow the same routes and the control of their stereoselectivity remains an arduous task.1
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Despite these synthetic difficulties, methods for the preparation of optically active P-stereogenic compounds have re-
cently received considerable attention. In particular, a number of procedures have been proposed with an intention to
offer to the community a general and convenient synthetic strategy.2 In such a perspective, phosphine oxides represent a
potential class of precursors with attractive features: they can lead to chiral phosphine ligands through a few well estab-
lished stereoselective step as well as be powerful trivalent ligands themselves. In contrast to most trivalent species, phos-
phine oxides are air- and moisture-stable and can be prepared on the large scale in racemic form. Still, the main synthetic
challenge relies in the synthetic accessibility of both enantiomers individually with high yields, high purities and through
straightforward procedures.3 Elegant works based on the chiral pool4 or stereospecific reduction of optically enriched P-
stereogenic phosphine oxides5 have been reported during the last few decades but generally allowed for the construction
of only one stereoisomer. In the last few months, significant breakthroughs in this area were reported by Minnaard and
co-workers, Berger and Monchamp, and Gilheany and co-workers.6 While these new methodologies still rely on the use of
enantiopure auxiliaries from the chiral pool to covalently or non-covalently transfer chiral information to the phosphorus
center through the formation of diastereoisomers, dynamic kinetic resolution and controlled inversion of the diastereose-
lectivity of key steps provided an access to both configurations of several pentavalent species with high isolated yields.
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We herein report the synthesis of a family of universal precursors of P-stereogenic phosphine oxides and of their triva-
lent derivatives. In complement to the approaches previously mentioned, this strategy relies on the straightforward multi-
gram scale chromatographic separation of both enantiomers of these phosphinates. These universal precursors do not
only display exceptional configurational and chemical stability but can also be converted into key P-stereogenic species
with high stereospecificities (Scheme 1).7
In previous studies, we have investigated (RP)-H-menthylphosphinates obtained by resolution as potential precursors
leading through straightforward procedures to optically active P-stereogenic phosphine oxides8 and phosphine-boranes.9
We therefore decided to evaluate the viability and versatility of an alternative yet unexplored strategy: accessing enanti-
opure P-stereogenic ligands from alkylphosphinates through preparative chiral chromatography in a perspective of pro-
cess development.10
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Preparative chiral chromatography has recently become a preferred method for rapidly acquiring enantiopure com-
pounds in the pharmaceutical and fine chemical industry.11 This technology has drawn an increasingly widespread interest
due to its cost effectiveness. In many instances, developing and executing a chromatographic enantioseparation is faster
and less labor-intensive than more traditional approaches for accessing enantiopurity. Additionally, solvent recycling and
effluent/side product reduction render this approach economically attractive and greener than alternative separation
techniques.
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Scheme 1. From P-stereogenic phosphinates to the galaxy of enantiopure P-stereogenic monodentate ligands.
SPO: secondary phosphine oxide; PiB: phosphinite borane; TPB: tertiary phosphine borane; TP: tertiary phosphine; SPB: sec-
ondary phosphine borane; PAB: phosphinous acid-borane.
RESULTS AND DISCUSSION
We began our study by the preparation of a series of H-alkoxyphenylphosphinates and screened the impact of the
alkoxy moiety on the chemical and configurational stability as well as the chromatographic resolution. Synthesis was
conducted from aryl-dichlorophosphine 1 with one equivalent of the alcohol in the presence of pyridine as a base followed
by gentle hydrolysis. The objective was to identify a low-cost alkoxy group, which, coupled to a readily available family of
trivalent chlorophosphine substrates bearing a broad range of side chains would lead to a family of air-, moisture- config-
urationally stable phosphinates that could be easily separated by chromatography on most usual chiral stationary phases.
In this field, it is considered that useful preparative HPLC separation typically have alpha of at least 1.2, and hopefully 1.5
or better.11
1. From a lead to a family and an ultimate precursor
Ethanol and isopropanol in the presence of pyridine afforded the desired primary and secondary alkoxyphosphinates in
95% yield, while the reaction failed with tert-butanol.12 While these P-stereogenic precursors could easily be separated by
chiral chromatography with selectivity ratio and resolution factors up to 1.5 and 7 respectively, they failed the tests in
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terms of configurational stability. In fact, analyses by chiral chromatography revealed a racemization process occurring on
a timescale of several minutes for the former and hours for the latter. This epimerization process, which was previously
observed and reported on menthol derivatives, seems symptomatic of primary and secondary alcohols (vide infra). Tert-
butylphenylphosphinate could be obtained from phenylphosphinic acid following the methodology developed by
Yiotakis13 and separated into stable individual enantiomers with a good purity. This candidate was also eliminated as a
possible universal precursor regarding the cost of the synthetic starting material and the poor versatility in terms of vari-
ants of the N,N-dimethylformamide di-tert-butyl acetal reactant.
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This preliminary round leads us to focus our efforts on tertiary alcohols. Following the synthetic pathway described
previously, 1-adamantanol afforded the desired H-adamantylphosphinate (±)-3a and (±)-3b from commercially available
dichlorophenylphosphine and o-tolyldichlorophosphine with 95% and 90% yield respectively (Table 1, entries 1 and 2).
These P-stereogenic adamantane-based model compounds appeared to fulfil the required criteria expected for universal
precursors. Pure and configurationally stable enantiomers (RP)-(+)-3a and (SP)-(–)-3a14 could easily be obtained by semi-
preparative chiral HPLC with separation and resolution factors up to 2.3 and 13 respectively (Chart 1)(See supporting in-
formation for detail).15
Chart 1. Chiral HPLC of H-adamantylphenylphosphinate (±)-3a
Analytical separation on Lux Cellulose-2 in hexane/ethanol (1/1) at 1 ml/min and 25°C with UV detection at 254 nm (black line)
and polarimeter (green line).
The remarkable and unusual ease to separate the enantiomers on most commercial chiral phases appeared to be specif-
ic to the 1-adamantyl substituent. In fact, while resolution factors of the ethylphenylphosphinate remained below 1.5 and
around 1 on most chiral phases, the values for the adamantylphenylphosphinate analogues were comprised between 1.2
and 2.3. Still, the versatility of this new family appeared to be restricted by the lack of available dichlorophosphine precur-
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sors. We therefore considered the synthesis of dichloro-adamantyloxyphosphine 2 as the universal precursor of this fami-
ly, by treating trichlorophosphine with 1-adamantanol. The desired product 2 was easily obtained in 75% yield and indeed
provided access to a large panel of H-adamantylalkyl- and H-adamantylarylphosphinates bearing functional groups 3a-h.
An extensive range of phosphinates 3 can be synthesized using both methodologies. Phosphinate 3d bearing n-butyl sub-
stituent was obtained with 29% yield due to difficult purification on silica gel (Table 1, entry 4) but secondary and tertiary
alkyl groups could be introduced with good yield (Table 1, entries 7 and 3). Arylphosphinates 3e,f,h were obtained with
moderate yield (Table 1, entries 5, 6 and 8) but the aryl substitution with electron withdrawing or donating group in ortho
or para position did not affect the formation of these phosphinates. Remarkably this whole series of H-
adamantylphosphinates 3a-h displayed excellent separation ratio and resolution factor on a broad range of stationary
phases.
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In addition to the parameters describing the separation, preparative chromatography is mostly concerned with produc-
tivity, which measures how much purified material can be prepared with a given quantity of stationary phase per unit
time. Semi-preparative equipment (1 cm diameter column) allowed the separation of 25 g of racemic mixture in 56 hours,
into 12 g of each enantiomers with excellent purity (3a : 25 g leading to SP-(−)-3a 12 g (45% yield), ee >99%, and RP-(+)-3a
12.4 g (47% yield), ee =98%). Similarly, the enantiomers (+)-3b-h and (–)-3b-h could be separated on the same scale as
straightforwardly with semi-preparative equipment.
Table 1. Synthetic pathways leading to H-adamantylphosphinates a
Entry
Reactant
Method
Product
Yieldb
95%c
O
P
I
H
Ph
O
1
1a
R = Ph
(±) 3a
I
O
P
H
2
3
1b
2
90%
75%
O
O
o-Tol
(±) 3b
R =o-Tolyl
O
P
II
H
t-Bu
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R = t-Bu
(±) 3c
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2
3
O
P
II
H
O
n-Bu
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5
2
2
29%
54%
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9
R = n-Bu
(±) 3d
O
P
H
O
II
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CO2Et
R = p-CO2Et(C6H4)
(±) 3e
O
P
H
O
MeO
II
6
7
2
2
57%
66%
R = o-OMe(C6H4)
(±) 3f
O
P
Cy
II
H
O
R = Cy
(±) 3g
II
8
2
57%
R = p-I(C6H4)
(±) 3h
a Reaction conditions: a) Adamantanol (1 equiv.), pyridine (1 equiv.), CH2Cl2, 0 °C to r.t., 12 h; b) H2O, 0 °C, 3 h; c) RMgX
THF, -60 °C to r.t., 12 h; d) EtOH (1 equiv.), r.t., 1 h; e) Semi-preparative chiral HPLC separation. b chemical yield after puri-
fication. c 3a was obtained in 49% yield using method II without optimization.
Having in hand a series of pure enantiomers with various electronic and steric properties, we examined their reactivity
in terms of straightforward conversion into P-stereogenic stable preligands such as SPO or protected monophosphines
2. Conversion of H-adamantylphosphinates into secondary phosphine oxides
Nucleophilic addition of organolithium reagent to enantiopure P-stereogenic phosphinate have been reported to lead
to enantioenriched SPO, an air and moisture stable family of pre-ligands displaying catalytic activity in cross-coupling
reactions.16 We were pleased to find that (RP)-3a with 3 equivalents of tert-BuLi at – 78 °C afforded tert-
butylphenylphosphine oxide (SP)-4a in 95% yield without racemization at the phosphorus atom in contrast to the reac-
tion carried out with pure (RP)-H-menthylphosphinate (RP)-3i (Scheme 2).
Scheme 2. Comparative conversion of H-alkylphosphinates into secondary phosphine oxides using secondary or
tertiary alcohol
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3 equiv t-BuLi,
THF, 3h, -80°C
O
1
2
3
O
P
P
H
H
O
Yield = 85%
4
5
4a
(SP)-
ee = 86 %
(
R )-3i
de = 99 %
P
6
7
8
O
3 equiv t-BuLi,
THF, 3h, -60°C
O
P
P
H
H
O
Yield = 95%
9
3a
(RP)-
ee = 99 %
S
4a
(
P)-
10
11
12
ee = 99 %
R = Ment fast
OLi
P
OLi
P
OLi
OLi
Ad
slow
t-BuLi
t-BuLi
13
P
P
Ph
Ph
RO
OR
Ph
RO-Li+
Ph
14
15
16
17
18
19
20
[(Rp)-3-Li]
[(Sp)-3-Li]
These results suggest that the substitution of adamantyloxy group on the deprotonated phosphinate [(RP)-3a-Li] pro-
ceeds more rapidly than its racemization. Thus, in the case of pure (RP)-3i, the loss of optical purity at low temperature
may be imputed to the presence of significant levels of lithium menthylate in the medium through competitive nucleo-
philic substitution on the phosphinate intermediate [(RP)-3i-Li]. The use of tertiary alcoholate as a leaving group excludes
this competitive substitution process (Scheme 2).
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This assumption was supported by the slow racemization process observed at low temperature on pure (RP)-3i which
was deliberately triggered by introduction of catalytic amounts of sodium menthylate.17 As for the performance of the
chromatographic enantioseparation, the nature of alkoxy group borne by phosphinates 3 appears to have a dramatic im-
pact on the stereoselectivity of subsequent nucleophilic substitutions on the phosphorus center leading to P-stereogenic
pre-ligands.
To confirm the robustness of this pathway leading to SPOs with reduced concomitant racemization, enantiomers (RP)-
3a and (SP)-3a were used as general substrates for substitution of the alkoxy moiety by a set of alkyl groups. As expected,
both enantiomers 4a-c were obtained with enantiomeric excesses > 90% (Table 2).
Table 2. Stereospecific synthesis of optically active SPO
Entry Phosphinate,
(%), R1Li
ee T°C,
timea
Yield [4] (%)b ee (%)c
1
(RP)-(+)-3a, 99
t-BuLi
-50, 2h
(SP)-(-)-4a,
99
99
80
2
(SP)-(-)-3a, 99
-50, 2h
(RP)-(+)-4a,
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t-BuLi
80
1
2
3
4
5
6
7
8
9
3
4
5
6
(RP)-(+)-3a, 99
n-BuLi
-50, 14h (SP)-(-)-4b,
92
92
91
80
(SP)-(-)-3a, 99
n-BuLi
-50, 14h (RP)-(+)-4b,
80
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(RP)-(+)-3a, 99
MeLi
-20, 3h
-20, 3h
(SP)-(-)-4c,
76
(SP)-(-)-3a, 99
MeLi
(RP)-(+)-4c,
90
78
a See supporting information for details; b Yield after purifica-
c
tion; Enantiomeric excess was determined by HPLC analysis
(see Supporting Information).
Substitution with tert-BuLi gave the best yields and enantiomeric excesses (Table 2, entries 1 and 2). However, when
enantiomerically pure 3a was treated with n-BuLi in THF at –78 °C, the reaction proceeds smoothly and the conversion
appeared to be complete at –50 °C after 14h. Under these conditions, the substitution of adamantyloxy group occurs with
a slight racemization yielding each enantiomer with 92% of ee (Table 2, entries 3 and 4). Same results were obtained with
MeLi at –20 °C (Table 2, entries 5 and 6). Unlike pathways based on resolution through formation of match-
ing/mismatching diastereoisomeric pairs, this strategy provides a straightforward access of both enantiomers of various
SPO and may thereby facilitate their use in asymmetric catalysis.
3. An entry to P-stereogenic monophosphines
To confirm the status of universal precursors of phosphinate 3, two reaction pathways leading to precursors of P-
stereogenic monophosphines were explored.
Taking advantage of the exceptionally slow rate of racemization of precursors 3 in basic conditions, phosphinous acid-
boranes 5 could be obtained with excellent ee from enantiopure 3a. To exemplify the potency of this convenient pathway,
phosphinous acid-boranes 5a and 5b bearing substituents with contrasted stereoelectronic features such as tert-butyl and
methyl groups were obtained with 99% and 88% ee respectively (Scheme 3). We, among others, have shown in previous
work18 that these compounds can be converted in two successive steps with excellent yields and enantiomeric excesses to
protected forms of secondary phosphine (secondary phosphine boranes), pre-ligands of widespread interest.19
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Scheme 3. One pot synthesis of phosphinous acid-boranes (+) or (–)-5a and (+) or (–)-5ba
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2
3
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5
6
7
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9
a
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Reagents and conditions: a) tert-BuLi (3 equiv.), −50°C, THF, 3 h or MeLi (3 equiv.), −20°C, THF, 3 h; b) TMSCl, −50°C or
−20°C to rt, THF; c) BH3 •SMe2, THF, 3 h; d) H2O, H+; e) TBAF, THF.
To access trivalent P-stereogenic compounds, an alternative pathway consisting in the non-racemizing cleavage of the
PO double bond, a major challenge in phosphorus chemistry,20 was designed. The strategy relies on the introduction of a
hydroxymethyl handle on the phosphorus center of phosphinates 3 in order to control the stereoselectivity of subsequent
PO reduction on resulting adducts with borane (Table 3).21 In that perspective, compounds 3a, 3c, 3f, and 3g were reacted
with formaldehyde to form optically pure phosphinates 6a, 6c, 6f and 6g. These P-stereogenic compounds indeed proved
to be excellent intermediates in the synthesis of highly optically enriched (ee > 95 %) phosphinite-boranes 7a, 7c, 7f and
7g by simple exposure to borane (Table 3).
Table 3. Conversion of optically pure 3 into hydroxymethylphosphinite-boranes 7a
Entry
Phosphinate, ee (%)b
(RP)-(+)-3a, 99
(SP)-(-)-3a, 99
(RP)-(+)-3c, >95
(SP)-(-)-3c, >95
(RP)-(+)-3e, 99
(SP)-(-)-3e, 99
(+)-3f, 99
Yield [6], ee (%)c
84 [(SP)-(+)-6a], 99
96 [(RP)-(-)-6a], 99
75 [(SP)-(-)-6c], >95
72 [(RP)-(+)-6c], >95
90 [(SP)-(+)-6e], >99
65 [(RP)-(-)-6e], >99
70 [(+)-6f], 99
Yield [7], ee (%)
1
86 [(RP)-(-)-7a], 99
84 [(SP)-(+)-7a], 96
51 [(RP)-(+)-7c],d >95
48 [(SP)-(-)-7c],d >95
2
3
4
5
6
7
8
9
e
/
e
/
81 [(-)-7f], 99
77 [(+)-7f], 99
73 [(+)-7g], >95
(-)-3f, 99
72 [(-)-6f], 98
(+)-3g, >95
94 [(-)-6g], >95
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10
(-)-3g, >95
85 [(+)-6g], >95
78 [(-)-7g], >95
1
2
3
a Reagents and conditions: a) (CH2O)n (1.5 equiv.), LiOH, THF/H2O, r.t., 3h; b) BH3•THF (6 equiv.), THF, r.t., 48h. b Yield after
4
5
c
d
e
purification. Enantiomeric excess was determined by HPLC analysis. Reaction time after the addition of BH3•THF was 96h.
6
7
Due to the presence of the ester group in R, the attempted borane reduction of 6e led to extensive ester reduction of starting
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material.
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The reaction is compatible with a wide variety of H-adamantylphosphinates and is stereoselective for all phosphinates
6a, 6c, 6f and 6g and phosphinite-boranes 7a, 7c, 7f and 7g (Table 3, entries 1-8). Phosphinate-borane 6c bearing a tert-Bu
substituent was the only member of the series to afford the expected 7c with moderate yield (Table 3, entry 3) due to the
competitive formation of secondary phosphine-borane.22 To our knowledge, this represents one of the very few example
of phosphinate P=O bond reduction with stereochemical control at phosphorus center.21 This reduction is controlled by
the presence of hydroxymethyl bound to phosphorus atom. A five-membered cyclic phosphonium intermediate was pro-
posed by Pietrusiewicz which further undergo hydride attack at phosphorus atom to deliver the phosphine-borane with
inversion of the configuration (Scheme 4).23
Scheme 4. Proposed mechanism for PO bond reduction with BH3.
Beyond the fundamental challenge that stereoselective PO cleavage represents, phosphinite-boranes 7 stand as key in-
termediates towards protected P-stereogenic monophosphines. To take advantage of the hydroxymethyl moiety intro-
duced we firstly examined the reactivity of phosphinite-borane 7a towards the substitution of the adamantyloxy group,
leading to a new family of hydroxymethyl phosphine-boranes with potential chelating features (Scheme 5). The utility of
the hydroxymethyl group both during the synthesis of phosphine or diphosphine ligand and for the coordination of the
resulting ligands with transition metal has been well established before.24
Scheme 5. Preparation of optically active hydroxymethylphosphine-boranes 8
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The Journal of Organic Chemistry
Confirming the advantage of the adamantyloxy as a leaving group affording substitutions without loss of the enantio-
meric excess, compound 7a reacted smoothly with primary alkyllithiums to give the corresponding phosphine-borane 8a
and 8b with inversion of configuration at the phosphorus atom (Scheme 5).25 However, as a consequence of the steric
hindrance of the substrate, tert-BuLi was not suitable for this reaction and only starting material was recovered after hy-
drolysis of the reaction medium.26
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Scheme 6. Substitution of the hydroxymethyl group on optically active phosphinite-boranes through oxidation-
substitutiona
a
Reagents and conditions: a) RuCl3 (20 mol%), K2S2O8 (3 equiv.), KOH (10 equiv.) CH3CN/H2O, 10h; b) n-BuLi (1.5 equiv.),
→
THF, −78 °C, 20 min; c) BnBr (4 equiv), −78 °C 0 °C, 4h.
Still, the versatility of the methodology based on adamantyloxy phosphinate precursors allowed to introduce the bulky
tert-Bu group directly on compound 3, which leads to 7c after hydroxymethylation and P=O cleavage. To further achieve
introduction of substituents of the phosphorus center, nucleophilic substitution must be replaced by oxidation into sec-
ondary phosphinite-borane 927 followed by nucleophilic substitution (Scheme 6). During these two steps, the hydroxyme-
thyl handle is the leaving group while the adamantyloxy is a spectator. 7c is therefore a key compound which displays
dual reactivity and leads through alternative pathways to new bulky P-stereogenic stable compounds that can be used in
asymmetric catalysis.
SUMMARY
In conclusion, semi-preparative chiral HPLC can lead to the straightforward multi-gram scale separation of H-
adamantylphosphinates as universal precursors bearing various substituents. These new objects provide an unprecedent-
ed access, through various types of substitution on the phosphorus center to both enantiomers of phosphine oxides and
boranes protected P-stereogenic ligands. Both enantiomers of optically enriched phosphine-boranes can be accessed
through a well-established route involving phosphinous-borane intermediates. Additionally, the same universal precursor
can lead to a new family of phosphinite-boranes 7, which display dual reactivity: the alkoxy or the hydroxymethyl substit-
uents can alternatively be replaced on demand by tailored substituents leading to new protected P-stereogenic phos-
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phines/phosphinites. We believe that these new classes of easily accessible enantioenriched precursors will contribute to
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the current renaissance of P-stereogenic ligands.
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EXPERIMENTAL SECTION
General Experimental Details.
9
All solvents were purified by standard procedures or obtained from a Solvent Purification System. Unless otherwise
mentioned, all reactions were carried out under an atmosphere of dry argon. Thin Layer Chromatography (TLC) was car-
ried out on silica gel 60 F254 and visualized under ultraviolet light (254 and 366 nm), or through spraying with 5% phos-
phomolybdic acid in EtOH, or by placing in iodine vapor. Flash chromatography was performed with silica gel 60 (230-
400 mesh). Solvents for chiral chromatography (n-hexane, n-heptane, 2-PrOH, EtOH, MeOH) are HPLC grade, degassed
and filtered on membrane 0.45µm before use. Lux Cellulose-2, Lux Amylose-2, (S,S)-Whelk-O1 and Chiralpak IA columns
(250*10mm) were used for semi-preparative separation. Lux Cellulose-2, Lux Cellulose-4, Lux Amylose-2, (S,S)-Whelk-O1,
Chiralcel OD-3 and Chiralpak AS-H, AZ-H, AD-H, IA columns (250*4.6mm) were used for the analytical separation. Chi-
ral HPLC analyses were performed with UV detector and polarimetric or circular dichroism (CD) detector. Retention
times Rt are given in minutes, retention factor ki = (Rti – Rt0)/Rt0 and enantioselectivity factor α = k2/k1. The sign given by
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the chiroptical detector is the sign of the enantiomer in the mobile phase used, at the specified wavelength.28 1H, C, P
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1
and B NMR spectra were recorded on spectrometers operating at 400 and 300 MHz for H. 13C and 31P nuclei were ob-
served with 1H decoupling. Unless otherwise specified NMR spectra have been made in CDCl3. As external reference for 31P
NMR spectra, 85% phosphoric acid was used. Chemical shifts (
δ δ =
) of 1H and 13C are reported in ppm relative to CHCl3 (
7.26 for 1H and = 77.0 for 13C) and C6D6 ( = 7.15 for 1H and = 128.02 for 13C). J values are given in Hz. Proton (1H) NMR
δ
δ
δ
information is given in the following format: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; sept; septet; m, mul-
tiplet), coupling constant J, number of protons). The prefix broad or b indicates the signal in question is broadened. Melt-
ing points (uncorrected) were determined in a capillary tube. [α]D25 values were determined with a Polarimeter, using a 10
cm length double jacketed cell: the sign (+) or (−) given for the described chiral compounds is the sign obtained at 589
nm in chloroform. High-resolution MS experiments were performed with an orthogonal acceleration time-of-flight (oa-
TOF) mass analyzer equipped with an electrospray ionisation (ESI) source. In the positive ion mode, the capillary voltage
was set at +5500 V and the cone voltage was set between 10-55 V. In MS, accurate mass measurements were performed
using two reference ions from a poly(ethylene glycol) or poly(propylene glycol) internal standard, according to a proce-
dure described elsewhere. Intensity data were collected on a diffractometer using graphitemonochromated MoKα radia-
tion (λ = 0.71073 Å) at 293 K. The collected frames were processed with the software HKL-2000, structures were solved by
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The Journal of Organic Chemistry
the direct methods, and refined using the SHELXL-97 software package. Compounds 4a-c,8 5a-b,9a 8a27 and 8b29 were
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known and characterizations data were in accordance with the literature.
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5
Main reason for the epimerization of (RP)-3i
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a) Reaction without sodium menthylate
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A dry Schlenk tube is charged under argon atmosphere with a solution of phosphinate (RP)-3i (de > 99%) (1 mmol) and
cooled down to −80°C in THF (5 mL). A solution of Lithium diisopropylamide (1 mmol, 2M in THF) in THF (2 mL) was
added dropwise, the reaction mixture was stirred at −80°C for 2h and the solution was hydrolyzed with THF/acetic acid;
9/1 at −80°C. The solution was allowed to warm to room temperature and water was added. A diastereomeric excess of
88% was determined by 31P NMR after extraction with diethyl ether.
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b) Reaction with sodium menthylate
A dry Schlenk tube is charged under argon atmosphere with a solution of phosphinate (RP)-3i (de > 99%) (1 mmol) and
cooled down to −80°C in THF (5 mL). A solution of Lithium diisopropylamide (1 mmol, 2M in THF) in THF (2 mL) was
added dropwise and after 5 min at this temperature, a solution of lithium menthylate (1 mmol in THF) (1mL), was also
added. The reaction mixture was stirred at −80°C for 2h and the solution was hydrolyzed with THF/acetic acid; 9/1 at
−80°C. The solution was allowed to warm to room temperature and water was added. A diastereomeric excess of 68% was
determined by 31P NMR after extraction with diethyl ether.
Synthesis of dichloro-adamantyloxyphosphine 2
A solution of 1-adamantanol (3.04 g, 20 mmol) in THF (15 mL) was added dropwise at -78°C to trichlorophosphine (1.75
mL, 20 mmol) in THF (15 mL). The solution was allowed to warm to room temperature and stirred overnight. Dichloro-
adamantyloxyphosphine 2 was isolated after bulb to bulb distillation (bp 110°C/0.08 mbar) in 75% yield (3.8 g). Air and
1
moisture sensitive white solid at 4°C: H NMR (400 MHz, C6D6): δ 1.22 (bs, 6H), 1.75 (bs, 3H), 1.89 (bs, 6H); 31P NMR (162
MHz, C6D6): δ 191.50 (s).
General procedure for the synthesis of racemic adamantylhydrogenophosphinate (Method I)
A solution of adamantanol (8.5 g, 56 mmol) and pyridine (4.5 mL, 56 mmol) in dichloromethane (100 mL) was added
dropwise at 0°C to a solution of dichloroarylphosphine (56 mmol) in dichloromethane (20 mL). After 15h at room temper-
ature, water (40 mL) was added slowly at 0°C. The two layers were separated and the aqueous phase was extracted with
hexane (3 x 20 mL). The organic layers were collected and concentrated under reduced pressure. Hexane (100 mL) was
added to the resulting crude and the organic phase was washed with aqueous sodium bicarbonate solution 10% (100 mL).
The aqueous phase was extracted with hexane (3 x 30 mL). The organic layers were collected, dried over MgSO4, filtrated,
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Page 14 of 25
and concentrated under reduced pressure to give adamantylhydrogenophenylphosphinate 3a and 3b in 95 % and 90%
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2
yield respectively.
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Adamantylhydrogenophenylphosphinate 3a. White solid, 14.7 g (95% yield), SP-(−)-3a [α]D25 −44.2 (c = 1.045, CHCl3), RP-
6
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25
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(+)-3a [α]D +44.3 (c = 1.07, CHCl3) : H NMR (200 MHz, CDCl3): δ 1.65 (bs, 6H), 2.13 (bs, 6H), 2.21 (bs, 3H), 7.44-7.56 (m,
3H), 7.79 (d, J = 553.3 Hz, 1H), 7.71-7.82 (m, 2H); 13C NMR (50 MHz, CDCl3): δ 30.7 (3C), 35.3 (3C), 43.7 (d, J = 4.9 Hz, 3C),
82.1 (d, J = 8.8 Hz), 128.1 (d, J = 13.8 Hz, 2C), 130.4 (d, J = 11.6 Hz, 2C), 131.3 (d, J = 137.5 Hz), 132.1 (d, J = 2.8 Hz); 31P NMR (81
MHz, CDCl3) : δ 15.2 (s). HRMS (ESI-MS) [M+H]+: found 277.1352; calculated for C16H22O2P+: 277.1351. Chiral HPLC: analyt-
ical separation on Lux Cellulose-2 in hexane/ethanol (1/1) at 1 ml/min and 25°C with UV detection at 254 nm and polari-
metric: Rt1 = 6.30 (SP)-(−), Rt2 = 11.12(RP)-(+), k1 = 1.1 (SP)-(−), k2 = 2.7 (RP)-(+), α = 2.46, Rs = 13.3. Semi-preparative separa-
tion on Lux-Cellulose-2 (250 x 10 mm) in methanol at 5 mL/min and 30°C with UV detection 235 nm, 0.1 mL of a 175
mg/mL racemic solution were injected every 2.4 min. After 700 injections, 6.0 g of (SP)-(−)-3a (ee >99%) and 6.2 g of (RP)-
(+)-3a (ee = 98%).
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Adamantylhydrogeno-o-tolylphosphinate 3b. White solid, 14.6 g (90% yield), (−)-3b [α]D −24.5 (c = 0.94, CHCl3), ee =
99%; (+)-3b [α]D25 +25.1 (c = 1.02, CHCl3), ee = 99%: 1H NMR (300 mHz, CDCl3): δ 1.65-1.67.(m, 6H), 2.14-2.15 (bs, 6H), 2.22
(bs, 3H), 2.57 (s, 3H), 7.21 – 7.25 (m, 1H), 7.30 (td, J = 7.4, 2.8 Hz, 1H), 7.44 (tt, J = 7.5, 1.5 Hz, 1H), 7.79 (ddd, J=16.1, 7.5, 1.3
13
Hz, 1H), 7.84 (d, J = 547.3 Hz, 1H); C NMR (100.6 MHz,CDCl3): δ 19.8 (d, J = 6.6 Hz), 30.8 (3C), 35.4 (3C), 43.7 (d, J = 4.9
Hz, 3C), 82.4 (d, J = 8.8 Hz), 125.4 (d, J = 14.3 Hz), 129.4 (d, J = 137 Hz), 130.7 (d, J = 11.5 Hz), 131.3 (d, J = 12.7 Hz), 132.1 (d, J =
31
2.7 Hz), 140.4 (d, J = 10.5 Hz); P NMR (121.5 MHz, CDCl3): δ 15.2 (s). HRMS (ESI-MS) [M+H]+: found 291.1508; calculated
for C17H24O2P+: 291.1512. Chiral HPLC: analytical separation on Lux Amylose-2 in hexane/ethanol (1/1) at 1 ml/min and 25°C
with UV detection at 220 nm and polarimetric: Rt1 = 5.60 (−), Rt2 = 8.94 (+), k1 = 0.87 (−), k2 = 1.98, α = 2.29, Rs = 8.38.
Semi-preparative separation on Lux-Amylose-2 (250 x 10 mm) in hexane/ethanol (1/1) at 5 mL/min and 30°C with UV de-
tection 220 nm, 0.6 mL of a 22 mg/mL racemic solution were injected every 12 min. After 100 injections, 670 mg of (−)-3b
(ee > 99%) and 660 mg of (+)-3b (ee > 99%).
General procedure for the synthesis of racemic adamantylhydrogenophosphinate (Method II)
A solution of aryl or alkyl magnesium bromide (8 mmol) in THF (2 mL) was added dropwise at −50°C to dichlo-
roadamantyloxyphosphine 2 (8 mmol) in hexane (2 mL) and the solution was allowed to warm to room temperature. Af-
ter 15h at room temperature, water (2 mL) was added slowly at 0°C. The two layers were separated and the aqueous phase
was extracted with hexane (3 x 5 mL). The organic layers were collected and concentrated under reduced pressure. Hex-
ane (5 mL) was added to the resulting crude and the organic phase was washed with aqueous sodium bicarbonate solu-
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The Journal of Organic Chemistry
tion 10% (5 mL). The aqueous phase was extracted with hexane (3 x 5 mL). The organic layers were collected, dried over
1
2
MgSO4, filtrated, and concentrated under reduced pressure to give adamantylhydrogenophosphinate 3c-h.
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Adamantylhydrogeno-tert-butylphosphinate 3c. White solid, 1.54 g (75% yield): (SP)-(−)-3c [α]D25 −19.4 (c = 1.03, CHCl3),
6
7
25
1
ee = 99%; (RP)-(+)-3c [α]D +19.6 (c = 1.1, CHCl3), ee = 99%: H RMN (400 MHz, CDCl3), δ 1.06 (d, J = 17.7 Hz, 9H), 1.62
8
9
(bm, 6H), 2.01 (bm, 6H), 2.17 (bs, 3H), 6.86 (d, J = 509.5 Hz, P-H); 13C NMR (75 MHz, CDCl3), δ 23.1 (3C), 30.9 (d, J = 99.9
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Hz), 31.2 (3C), 36.0 (3C), 44.0 (d, J = 4.4 Hz, 3C), 81.6 (d, J = 10.5 Hz); P NMR (161 MHz, CDCl3): δ 37.5 (s). HRMS (ESI-
MS) [M+H]+: found 257.1665; calculated for C14H26O2P+: 257.1666. Chiral HPLC: analytical separation on (S,S)-Whelk-O1 in
hexane/isopropanol (7/3) at 1 ml/min and 25°C with polarimetric detection: Rt1 = 7.32 (SP)-(−), Rt2 = 10.89 (RP)-(+), k1 = 1.29
(SP)-(−), k2 = 2.4 (RP)-(+), α = 1.87, Rs = 7.79. Semi-preparative separation on (S,S)-Whelk-O1 (250 x 10 mm) in hex-
ane/isopropanol (7/3) at 5 mL/min with polarimetric detection, 0.15 mL of a 384 mg/mL racemic solution were injected
every 5 min. After 26 injections, 720 mg of (−)-3c (ee > 95%) and 735 mg of (+)-3c (ee > 95%).
Adamantylhydrogeno-n-butylphosphinate 3d. Colorless oil, 743 mg (29% yield), (−)-3d [α]D25 −1.7 (c = 1.105, CHCl3) ee =
99%, (+)-3d [α]D25 +1.8 (c = 1.05, CHCl3) ee = 99%: 1H NMR (400 MHz, CDCl3) δ 0.85 (t, J = 7.1 Hz, 3H), 1.35 (dq, J = 14.6, 7.1
Hz, 2H), 1.41-1.53 (m, 2H), 1.58 (t, J = 3.0 Hz, 6H), 1.60-1.70 (m, 2H), 1.96-2.02 (m, 6H), 2.13 (bs, 3H), 7.23 (d, J = 521 Hz, 1H);
13C NMR (101 MHz, CDCl3) δ 13.5, 23.0 (d, J = 2.2 Hz), 23.4 (d, J = 16.1 Hz), 29.1 (d, J = 97.6 Hz), 30.9 (3C), 35.6 (3C), 43.8 (d,
J = 4.4 Hz, 3C), 81.2 (d, J = 8.8 Hz); 31P NMR (162 MHz, CDCl3) δ 28.5 (s). HRMS (ESI-MS) [M+H]+: found 257.1665; calcu-
lated for C14H26O2P+: 257.1665. Chiral HPLC: analytical separation on (S,S)-Whelk-O1 in hexane/isopropanol (7/3) at 1
ml/min and 25°C with polarimetric detection: Rt1 = 10.87 (−), Rt2 = 12.57 (+), k1 = 2.62 (−), k2 = 3.19, α = 1.22, Rs = 4.18. Semi-
preparative separation on (S,S)-Whelk-O1 (250 x 10 mm) in hexane/isopropanol (7/3) at 5 mL/min with polarimetric de-
tection, 0.11 mL of a 105 mg/mL racemic solution were injected every 4 min. After 35 injections, 166 mg of (−)-3d (ee >
95%) and 198 mg of (+)-3d (ee > 95%).
25
Adamantylhydrogeno-4-(ethyloxycarbonyl)phenylphosphinate 3e. White solid, 752 mg (54% yield): (SP)-(−)-3e [α]D
−21.7 (c = 1.065, CHCl3) (RP)-(+)-3e [α]D25 +22.2 (c = 1.11, CHCl3) White solid : 31P NMR (162 MHz, CDCl3) δ 13.1 (s); 1H NMR
(400 MHz, CDCl3) δ 1.40 (t, J = 7.1 Hz, 3H), 1.65 (t, J = 3.0 Hz, 6H), 2.12 (d, J = 3.0 Hz, 6H), 2.21 (bs, 3H), 4.39 (q, J = 7.3 Hz,
2H), 7.82 (d, J = 560 Hz, 1H), 7.84 (dd, J = 13.3, 8.0 Hz, 2H), 8.13 (dd, J = 8.1, 2.9 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 14.2,
31.1 (3C), 35.6 (3C), 44.2 (d, J = 4.4 Hz, 3C), 61.4, 83.4 (d, J = 8.8 Hz), 129.4 (d, J = 13.9 Hz, 2C), 130.9 (d, J = 11.7 Hz, 2C), 134.0
(d, J = 2.9 Hz), 136.3 (d J = 135.0 Hz), 165.7; HRMS (ESI-MS) [M+H]+: found 349.1563; calculated for C19H26O4P+: 349.1565.
Chiral HPLC: analytical separation on Chiralpak AD-H in hexane/ethanol (1/1) at 1 ml/min and 25°C with UV detection at
254 nm and polarimeter: Rt1 = 7.91 (RP)-(+), Rt2 = 9.38 (SP)-(−), k1 = 1.64 (RP)-(+), k2 = 2.13 (SP)-(−), α = 1.30, Rs = 2.39. Semi-
preparative separation on Chiralpak IA (250 x 10 mm) in hexane/ethanol (1/1) at 5 mL/min and 30°C with UV detection
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280 nm, 0.19 mL of a 42.5 mg/mL racemic solution were injected every 4 min. After 45 injections, 152 mg of (SP)-(−)-3e (ee
> 99%) and 179 mg of (RP)-(+)-3e (ee > 99%).
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Adamantylhydrogeno-o-anisylphosphinate 3f. White solid 1.75 g (57% yield): (−)-3f [α]D −57.1 (c = 0.925, CHCl3) ee =
6
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25
1
99%, (+)-3f [α]D +57.0 (c = 0.95, CHCl3) ee = 99%; H NMR (400 MHz, CDCl3) δ 1.58 (t, J = 3.14 Hz, 6H), 2.04 (d, J = 3.01
Hz, 6H), 2.13 (bs, 3H), 3.81 (s, 3H), 6.85 (dd, J = 8.03, 6.78 Hz, 1H), 6.99 (td, J = 7.40, 2.51 Hz, 1H), 7.39 (d, J = 573 Hz, 1H),
7.41-7.47 (m, 1H), 7.75 (ddd, J = 14.49, 7.47, 1.63 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 31.1 (3C), 35.8 (3C), 44.1 (d, J = 4.4 Hz,
3C), 55.6, 81.9 (d, J = 8.8 Hz), 110.8 (d, J = 6.6 Hz), 119.6 (d, J = 138.6 Hz), 120.7 (d, J = 13.2 Hz), 133.1 (d, J = 6.6 Hz), 134.2 (d, J
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= 1.5 Hz), 161.1 (d, J = 4.4 Hz); P NMR (162 MHz, CDCl3) δ 10.30 (s). HRMS (ESI-MS) [M+H]+: found 307.1458; calculated
for C17H24O3P+: 307.1458. Chiral HPLC: analytical separation on Lux-Cellulose-2 in heptane/ethanol (1/1) at 1 ml/min and
25°C with UV detection at 254 nm and polarimeter: Rt1 = 7.20 (−), Rt2 = 10.83 (+), k1 = 1.40 (−), k2 = 2.61, α = 1.86, Rs = 9.01.
Semi-preparative separation on Lux-Cellulose-2 (250 x 10 mm) in hexane/ethanol (1/1) at 5 mL/min and 30°C with polari-
metric detection, 0.4 mL of a 50 mg/mL racemic solution were injected every 6 min. After 70 injections, 752 mg of (−)-3f
(ee > 99%) and 726 mg of (+)-3f (ee > 98%).
Adamantylhydrogeno-cyclohexylphosphinate 3g. White solid, 1.49 g (66% yield): (−)-3g [α]D25 −20.3 (c = 0.92, CHCl3), ee
= 99%, (+)-3g [α]D25 +19.4 (c = 1.01, CHCl3) ee =99%: 31P NMR (162 MHz, CDCl3) δ 31.9 (s); 1H NMR (400 MHz, CDCl3) δ 1.18-
1.34 (m, 5H), 1.63 (bs, 6H), 1.65-1.74 (m, 2H), 1.78-1.99 (m, 4H), 2.01-2.07 (m, 6H), 2.18 (bs, 3H), 7.01 (dd, J = 513, 1.8 Hz, 1H);
13C NMR (101 MHz, CDCl3) δ 24.4 (d, J = 2.2 Hz), 24.6 (d, J = 1.5 Hz), 25.3, 25.8 (d, J = 2.2 Hz), 25.9 (d, J = 2.2 Hz), 31.0 (3C),
35.8 (3C), 37.4 (d, J = 100 Hz) 43.9 (d, J = 4.4 Hz, 3C) 80.9 (d, J = 9.5 Hz). HRMS (ESI-MS) [M+H]+: found 283.1821; calcu-
lated for C16H28O2P+: 283.1822. Chiral HPLC: analytical separation on (S,S)-Whelk-O1 in hexane/isopropanol (7/3) at 1
ml/min and 25°C with polarimetric detection: Rt1 = 9.93 (−), Rt2 = 12.01 (+), k1 = 2.31 (−), k2 = 3.00, α = 1.30, Rs = 2.67. Semi-
preparative separation on (S,S)-Whelk-O1 (250 x 10 mm) in hexane/isopropanol (7/3) at 5 mL/min with polarimetric de-
tection, 0.18 mL of a 88 mg/mL racemic solution were injected every 3.5 min. After 75 injections, 583 mg of (−)-3g (ee >
95%) and 508 mg of (+)-3g (ee > 95%).
25
Adamantylhydrogeno-4-iodophenylphosphinate 3h. White solid 917 mg (57% yield): (−)-3h [α]D −28.5 (c = 0.965,
CHCl3) ee = 99%, (+)-3h [α]D25 +28.4 (c = 1.00, CHCl3) ee = 99%; 1H NMR (400 MHz, CDCl3) δ 1.68 (t, J = 3.0 Hz, 6H), 2.14
(d, J = 3.3 Hz, 6H), 2.24 (bs, 3H), 7.46-7.55 (m, 2H), 7.77 (d, J = 559 Hz, 1H), 7.85-7.90 (m, 2H); 13C NMR (101 MHz, CDCl3) δ
31.1 (3C), 35.7 (3C), 44.2 (d, J = 4.4 Hz, 3C), 83.2 (d, J = 8.8 Hz), 100.3 (d, J = 3.7 Hz), 131.3 (d, J = 137.9 Hz), 132.3 (d, J = 11.7
Hz, 2C), 137.8 (d, J = 13.9 Hz, 2C); 31P NMR (162 MHz, CDCl3) δ 13.3 (s). HRMS (ESI-MS) [M+H]+: found 403.0315; calculated
for C16H21O2PI+: 403,0318. Chiral HPLC: analytical separation on Lux-Amylose-2 in heptane/ethanol (1/1) at 1 ml/min and
25°C with UV detection at 254 nm and polarimeter: Rt1 = 8.00 (−), Rt2 = 15.79 (+), k1 = 1.67 (−), k2 = 4.26 (+), α = 2.55, Rs =
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13.05 or on Chiralpak AD-H in hexane/ethanol (1/1) at 1 mL/min and 25°C with UV detection at 254 nm and polarimeter:
Rt1 = 7.13 (+), Rt2 = 8.61 (−), k1 = 1.38 (+), k2 = 1.87 (−), α = 1.35, Rs = 3.17. Semi-preparative separation on Lux-Amylose-2
(250 x 10 mm) in ethanol at 3 mL/min and 30°C with UV detection 254 nm, 0.95 mL of a 27.5 mg/mL racemic solution
were injected every 35 min. After 21 injections, 248 mg of (−)-3h (ee > 99%) and 269 mg of (+)-3h (ee = 99%).
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General procedure for the synthesis of optically active SPO 4a-c
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A dry Schlenk tube is charged under argon atmosphere with a solution of alkyllithium (2.2 mmol) in THF (5 mL) and
cooled down to −50°C. A solution of phosphinate 3a (1 mmol) in THF (2 mL) was added dropwise, the reaction mixture
was stirred at −50°C for 2h and the solution was allowed to warm to −20°C. The reaction mixture was stirred at this tem-
perature for 3h. The reaction mixture is then diluted with Et2O (5 mL) and NH4Cl saturated aqueous solution (5 mL). The
organic phase was separated off, and the aqueous phase was extracted with AcOEt (2 × 5 mL). The combined organic lay-
ers were dried (MgSO4), filtered, concentrated under vacuum. Purification of the crude by chromatography on a short
plug of deactivated silica gel (10 % H2O) using Et2O/light petroleum/MeOH 4/1/0.05 as eluent, afforded SPO 4.
General procedure for synthesis of phosphinous acid-boranes 5a,b
A dry Schlenk tube is charged under argon atmosphere with a solution of alkyllithium (2.2 mmol) in THF (5 mL) and
cooled down to −50°C. A solution of phosphinate 3a (1 mmol) in THF (2 mL) was added dropwise, the reaction mixture
was stirred at −50°C for 2h and the solution was allowed to warm to −20°C. After stirring the reaction mixture 2h at this
temperature, trimethylsilyl chloride (279 μL, 2.2 mmol) was added and the solution was allowed to warm to room tem-
31
perature. The reaction was monitoring by P NMR. Then, BH3.SMe2 (208 μL, 2.2 mmol) was added at room temperature.
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After 3 hours, the completion of the reaction was confirmed by P NMR. Aqueous HCl (5 %) was added under vigorous
stirring. The aqueous layer was washed with dichloromethane (3 x 10 mL). The organic layers were combined and volatiles
were removed under vacuum. The residue was dissolved in THF and tetra-n-butylammonium fluoride (1 M solution in
THF, 0.6 mmol) was added under vigorous stirring. The residue was dissolved in diethyl ether. Aqueous NaOH (10 %) was
added under vigorous stirring until pH>10. The organic layer was extracted with water and the combined aqueous layers
were washed twice with diethyl ether. Aqueous HCl (5 %) was added dropwise until pH<1. The product was extracted
with diethyl ether (3 x 10 mL). The organic layers were washed with brine, dried over Na2SO4 and volatiles were removed
under vacuum. Phosphinous acid-boranes 5a,c proved to be stable to air and moisture. However, neat compound proved
to lose their BH3 moieties to afford the corresponding secondary phosphine oxide. This undesirable transformation also
occurred upon prolonged exposition to high vacuum. Thus 5a,c were preferentially stored in solution and “neat” samples
usually featured trace amounts of solvents.
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General procedure for the synthesis of optically active phosphinates 6
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To a suspension of (adamantyl)(hydrogeno)phosphinate 3a,c,e,f,g (0.5 mmol) and paraformaldehyde (1.5 equiv., 23 mg,
0.75 mmol) in THF (20mL) was added dropwise the solution of LiOH.H2O (30 mol%) in water (0.5 mL) under stirring
conditions. The mixture was further stirred for 3h at room temperature. The obtaining solution was diluted with water
(20 mL) and was neutralized with saturated NH4Cl aqueous solution. The product was extracted with CH2Cl2 (3 x 20 mL)
and the combined organic layers were dried over anhydrous Na2SO4 and were evaporated to dryness under reduced pres-
sure. The residue was purified by column chromatography on deactivated silica gel (10 wt% H2O) with Et2O, CH2Cl2 or
AcOEt as eluent or by slow crystallization into CH2Cl2/Et2O mixture at −20°C.
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Adamantyl(hydroxymethyl)phenylphosphinate 6a. Single crystal growth for X-ray molecular structure determination
was carried out into CH2Cl2/n-hexane solution at low temperature (−20°C). White solide, 0.147 g (96% yield). (RP)-(−)-6a
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[α]D −23.7 (c = 0.55, CHCl3), ee = 99%; (SP)-(+)-6a [α]D +22.8 (c = 0.6, CHCl3), ee = 99%; H NMR (400 MHz, CDCl3)
1.60 (bs, 6H), 1.99-2.10 (m, 6H), 2.13 (bs, 3H), 3.91 (bd, J = 14.5 Hz, 1H), 3.99 (dd, J = 14.5 Hz, J = 6.3 Hz, 1H), 4.4 (bs, 1H),
7.43-7.51 (m, 2H), 7.51-7.59 (m, 1H), 7.79-7.88 (m, 2H); 13C{1H} NMR (75 MHz, CDCl3)
30.9 (3C), 35.4 (3C), 44.1 (d, J = 3.30
Hz, 3C), 61.2 (d, J = 118.5 Hz), 82.8 (d, J = 9.9 Hz), 128.0 (d, J = 12.1 Hz, 2C), 131.5 (d, J = 9.9 Hz, 2C), 131.7 (d, J = 2.7 Hz), 131.8
(d, J = 123.3 Hz); 31P{1H} NMR (162 MHz, CDCl3)
33.1 (s); HRMS (ESI-MS) [M+H]+: found 307.1456; calculated for
δ
δ
δ
C17H24PO3+ 307.1458. Chiral HPLC: analytical separation on Lux-Cellulose-2 in hexane/ethanol (1/1) at 1 ml/min and 25°C
with UV detection at 254 nm and polarimeter: Rt1 = 5.91 (RP)-(−), Rt2 = 9.11 (SP)-(+), k1 = 0.97 (−), k2 = 2.04 (+), α = 2.10, Rs
= 7.81.
Adamantyl-t-butyl(hydroxymethyl)phosphinate 6c. Purification by column chromatography using AcOEt as eluent (Rf
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= 0.3) or recrystallization in Et2O at -18°C. White solid, 0.449 g (82% yield). (SP)-(−)-6c [α]D −3.0 (c = 0.51, CHCl3), ee =
99%; (RP)-(+)-6c [α]D25 +3.1 (c = 0.52, CHCl3), ee = 99%; 1H NMR (400 MHz, CDCl3)
δ 1.17 (d, J = 15.2 Hz, 9H), 1.63 (bs, 6H),
2.07 (bs, 6H) 2.17 (bs, 3H), 3.57 (bs, 1H), 3.83 (dd, J = 14.3 Hz, J = 7.0 Hz, 1 H), 3.97 (d, J = 14.3 Hz, 1 H); 13C NMR (101 MHz,
CDCl3) δ 24.20, 31.2 (3C), 32.5 (d, J = 93.9 Hz), 35.8 (3C), 44.4 (d, J = 2.9 Hz, 3C), 58.1 (d, J = 91.7 Hz), 81.9 (d, J = 11.00 Hz);
31P NMR (162 MHz, CDCl3) δ 53.5 (s); HRMS (ESI-MS) [M+Na]+: found 309.1591; calculated for C15H27O3PNa+ 309.1590. Chi-
ral HPLC: analytical separation on Chiralcel OD-3 in hexane/isopropanol (95/5) at 1 ml/min and 25°C with UV detection
at 205 nm and polarimeter: Rt1 = 4.96 (RP)-(+), Rt2 = 5.59 (SP)-(−), k1 = 0.65 (RP)-(+), k2 = 0.86 (SP)-(−), α = 1.32, Rs = 1.92.
Adamantyl(hydroxymethyl)4-(ethyloxycarbonyl)phenylphosphinate 6e. Purification by column chromatography using
Et2O as eluent (Rf = 0.25). White solid 176 mg (90% yield). (RP)-(−)-6e [α]D25 −33.6 (c = 0.81, CHCl3), ee = 99%; (SP)-(+)-6e
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1
[α]D +33.4 (c = 0.82, CHCl3), ee = 99%; H NMR (300 MHz, CDCl3)
δ 1.42 (t, J = 7.15 Hz, 3H), 1.59 (bs, 6H), 1.97 - 2.10 (m,
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6H), 2.14 (bs, 3H), 2.76 - 2.85 (m, 1H), 3.87 - 4.04 (m, 2H), 4.42 (q, J = 7.15 Hz, 2H), 7.93 (dd, J = 11.19, 8.25 Hz, 2H), 8.14 (dd,
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13
J = 8.25, 3.12 Hz, 2H); C NMR (101 MHz, CDCl3)
δ 14.3, 31.2 (3C), 35.6 (3C), 44.5 (d, J = 3.7 Hz, 3C), 61.4, 61.5 (d, J = 117.4
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7
Hz), 84.1 (d, J = 9.5 Hz), 129.3 (d, J = 12.5 Hz, 2C), 131.8 (d, J = 9.5 Hz, 2C), 133.8 (d, J = 2.9 Hz), 136.8 (d, J = 121.7 Hz), 165.9;
31P NMR (121 MHz, CDCl3) 31.5; HRMS (ESI-MS) [M+H]+: found 379.1669; calculated for C20H28O5P+ 379.1669. Chiral
δ
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HPLC: analytical separation on Chiralcel OD-3 in hexane/isopropanol (95/5) at 1 ml/min and 25°C with UV detection at
205 nm and polarimeter: Rt1 = 6.89 (−), Rt2 = 8.96 (+), k1 = 1.30 (−), k2 = 1.99 (+), α = 1.53, Rs = 4.89.
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Adamantyl-o-anisyl(hydroxymethyl)phosphinate 6f. Purification by column chromatography using Et2O as eluent (Rf =
0.12). White solid 0.405 g (72% yield). ). (−)-6f [α]D25 −71.2 (c = 1.07, CHCl3), ee = 99%; (+)-6f [α]D25 +71.0 (c = 1.10, CHCl3),
1
ee = 99%; H NMR (400 MHz, CDCl3)
δ 1.56 (bs, 6H), 1.93-2.03 (m, 6H), 2.09 (bs, 3H), 3.89 (s, 3H), 4.03 (dd, J = 14.3 Hz, J =
6.4 Hz, 1H), 4.08 (dd, J = 14.3, 3.8 Hz, 1H), 6.93 (dd, J = 7.90, 6.15 Hz, 1H) 7.07 (bt, J = 7.1, 1 H), 7.2 (bt, J = 7.5 Hz, 1H), 7.96
(ddd, J = 12.91, 7.50, 1.54 Hz, 1 H); 13C NMR (101 MHz, CDCl3)
31.1 (3C), 35.7 (3C), 44.3 (d, J = 3.7 Hz, 3C), 55.5, 61.6 (d, J =
116.6 Hz), 82.69 (d, J = 10.3 Hz), 110.8 (d, J = 7.3 Hz), 120 (d, J = 121 Hz), 120.9 (d, J = 11.7 Hz), 134.2 (d, J = 2.2 Hz), 135.3 (d, J =
6.6 Hz), 160.7 (d, J = 5.14 Hz); 31P NMR (162 MHz, CDCl3)
31.4 (s); HRMS (ESI-MS) [M+H]+: found 337.1563; calculated for
δ
δ
C18H26O4P+ 337.1563. Chiral HPLC: analytical separation on Chiralpak AZ-H in heptane/ethanol (8/2) at 1 ml/min and 25°C
with UV detection at 254 nm and CD at 254 nm: Rt1 = 9.22 (+), Rt2 = 10.18 (−), k1 = 2.07 (+), k2 = 2.39 (−), α = 1.15, Rs = 1.81.
Adamantyl(cyclohexyl)(hydroxymethyl)phosphinate 6g. Purification by column chromatography using Et2O as eluent
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(Rf = 0.12). White solid 0.353 g (94% yield). (−)-6g [α]D −2.01 (c = 0.7, CHCl3), ee > 95%; (+)-6g [α]D +1.6 (c = 0.87,
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CHCl3), ee > 95%; H NMR (400 MHz, CDCl3)
δ 1.17-1.45 (m, 5H), 1.63 (bs, 6H), 1.67-2.03 (m, 6H), 2.05 (bs, 6 H), 2.17 (bs,
3H), 3.77-3.88 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 24.9 (d, J = 2.9 Hz), 25.4 (d, J = 3. 7 Hz), 25.9 (d, J = 1.5 Hz), 26.2 (d, J =
3.7 Hz), 26.3 (d, J = 3.7 Hz), 31.1 (3C), 35.7 (3C), 37.1 (d, J = 93.9 Hz), 44.5 (d, J = 2.9 Hz, 3C), 59.1 (d, J = 98.3 Hz), 81.7 (d, J =
10.3 Hz); 31P NMR (162 MHz, CDCl3)
δ
49.5 (s); HRMS (ESI-MS) [M+H]+: found 313.1927; calculated for C17H30O3P+ 313.1927.
Chiral HPLC: analytical separation on Chiralpak AD-H in heptane/ethanol (95/5) at 1 ml/min and 25°C with UV detection
at 220 nm and polarimeter: Rt1 = 12.16 (+), Rt2 = 14.59 (−), k1 = 3.05 (+), k2 = 3.86 (−), α = 1.27, Rs = 3.51.
General procedure for the synthesis of tertiary optically pure phosphinite-boranes 7
To a solution of 6a,c,e,g (0.6 mmol) in THF (3 mL) was slowly added the solution of BH3 (1M in THF) (3.6 mmol, 6
equiv., 3.6mL) at room temperature under stirring conditions. The mixture was further stirred for 48h-96h at room tem-
perature. The resulting solution was evaporated under reduced pressure to give the oil liquids which were quenched with
saturated NaHCO3 aqueous solution at 0°C. The products were extracted with CH2Cl2 (10mL x 3). The combined organic
31
layers were dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. P NMR analysis of the
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crude mixture had shown the presence of secondary phosphine-borane as by-product (Table S1). The residue was purified
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by the silica gel chromatography using AcOEt/n-hexane or CH2Cl2 as eluent.
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Adamantyl(hydroxymethyl)phenylphosphinite borane 7a. Purification by column chromatography using hexane/AcOEt
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(9/1) as eluent (Rf = 0.1). White solid 1.57 g (86% yield). (RP)-(−)-7a [α]D −112.6 (c = 0.5, CHCl3), ee = 99%; (SP)-(+)-7a
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[α]D25 +132.1 (c = 0.5, CHCl3), ee = 96%; 1H NMR (400 MHz, CDCl3)
δ 0.51 - 1.41 (bm, 3H), 1.58 (t, J = 3.0 Hz, 6H), 2.00 (d, J =
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3.0 Hz, 6H), 2.14 (bs, 3H), 3.92 - 4.02 (m, 2H), 7.46 - 7.52 (m, 2H), 7.52 - 7.58 (m, 1H), 7.83 - 7.91 (m, 2H); 13C NMR (75
MHz, CDCl3)
2C), 131.1 (d, J=10.45 Hz, 2C), 131.6 (d, J = 55.0 Hz), 131.8 (d, J=2.20 Hz); P NMR (162 MHz, CDCl3)
NMR (128 MHz, CDCl3)
-39.1 (bd, J = 62.3 Hz); HRMS (ESI-MS) [M-H]-: found 289.1539; calculated for C16H23BO2P-
δ 31.0 (3C), 35.4 (3C), 43.7 (d, J = 3.8 Hz, 3C), 63.8 (d, J = 55.0 Hz), 82.5 (d, J = 6.6 Hz), 128.3 (d, J = 9.9 Hz,
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δ
93.8 - 95.6 (bm); B
δ
289.1537. Chiral HPLC: analytical separation on Chiralcel OD-3 in hexane/isopropanol (95/5) at 1 ml/min and 25°C with
UV detection at 254 nm and polarimeter: Rt1 = 6.58 (RP)-(−), Rt2 = 7,52 (SP)-(+), k1 = 1.19 (RP)-(−), k2 = 1.51 (SP)-(+), α = 1.26,
Rs = 2.38.
Adamantyl-t-butyl(hydroxymethyl)phosphinite borane 7c. Purification by column chromatography using hex-
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ane/AcOEt (9/1) as eluent (Rf = 0.4). White solid 0.29 g (51% yield). (SP)-(−)-7c [α]D −4.3 (c = 0.99, CHCl3), ee > 95%;
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(RP)-(+)-7c [α]D +4.2 (c = 0.93, CHCl3), ee > 95%: H NMR (400 MHz, CDCl3)
9H), 1.63 (t, J = 3.07 Hz, 6H), 1.97 – 2.08 (m, 6 H), 2.19 (bs, 3H), 3.91 (dd, J = 13.9, 2.3 Hz ,1H), 4.01 (dd, J = 13.9, 2.6 Hz, 1H);
13C NMR (101 MHz, CDCl3)
24.7 (d, J = 2.2 Hz, 3C), 31.23 (3C), 31.8 (d, J = 42.5 Hz), 35.72 (3C), 43.93 (d, J = 2.93 Hz, 3C),
60.2 (d, J = 37.4 Hz), 81.7 (d, J = 8.7 Hz); 31P NMR (162 MHz, CDCl3) 116.8 (bm); 11B NMR (128 MHz, CDCl3)
-41.3 (d, J =
δ 0.21 – 1.09 (bm, 3H), 1.19 (d, J = 13.90 Hz,
δ
δ
δ
61.5 Hz); HRMS (ESI-MS) [M+Na]+: found 307.1969; calculated for C15H30BO2PNa+ 307.1972. Chiral HPLC: analytical sepa-
ration on Lux-Cellulose-4 in heptane/isopropanol (95/5) at 1 ml/min and 25°C with UV detection at 220 nm and polarime-
ter: Rt1 = 5.50 (SP)-(−), Rt2 = 6.80 (RP)-(+), k1 = 0.83 (SP)-(−), k2 = 1.27 (RP)-(+), α = 1.53, Rs = 5.08.
Adamantyl-o-anisyl(hydroxymethyl)phosphinite borane 7f. Purification by column chromatography using hex-
ane/AcOEt (6/4) as eluent (Rf = 0.23). White solid 124 mg (81% yield). (−)-7f [α]D25 −99.2 (c = 0.95, CHCl3), ee = 99%; (+)-
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7f [α]D +98.5 (c = 0.95, CHCl3), ee = 99%: H NMR (400 MHz, CDCl3)
6H), 2.11 (bs, 3H), 3.92 (s, 3H), 4.21-4.30 (m, 2H), 6.96 (dd, J = 8.34, 3.22 Hz, 1H), 7.07 (tdd, J = 7.46, 7.46, 2.20, 0.88 Hz, 1
H), 7.53 (dddd, J = 8.34, 7.46, 1.61, 0.88 Hz, 1H), 7.96 (ddd, J = 13.54, 7.54, 1.61 Hz, 1H); 13C NMR (101 MHz, CDCl3)
31.2
(3C), 35.7 (3C), 43.9 (d, J = 3.67 Hz, 3C), 55.6 (3C), 62.7 (d, J = 55.7 Hz), 82.2 (d, J = 7.3 Hz), 111.1 (d, J = 4.40 Hz), 119.5 (d, J =
51.3 Hz), 121.2 (d, J = 11.7 Hz), 134.3 (d, J = 2.2 Hz), 135.7 (d, J = 16.1 Hz), 161.2; 31P NMR (162 MHz, CDCl3)
96.9–98.7 (bm);
11B NMR (128 MHz, CDCl3)
-38.3 (bd, J = 65.4 Hz); HRMS (ESI-MS) [M+Na]+: found 357.1768; calculated for
δ 0.5-1.37 (m, 3H), 1.52-1.61 (m, 6H), 1.91-1.99 (m,
δ
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C18H28BO3PNa+ 357.1765. Chiral HPLC: analytical separation on Chiralpak AS-H in heptane/ethanol (9/1) at 1 ml/min and
25°C with UV detection at 254 nm and polarimeter: Rt1 = 6.17 (−), Rt2 = 8.37 (+), k1 = 1.06 (−), k2 = 1.79 (+), α = 1.69, Rs = 4.
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Adamantyl(cyclohexyl)(hydroxymethyl)phosphinite borane 7g. Purification by column chromatography using CH2Cl2 as
eluent (Rf = 0.5). White solid 114 mg (78% yield). (−)-7g [α]D25 −4.1 (c = 0.99, CHCl3), ee > 95%; (+)-7g [α]D25 +4.0 (c = 0.98,
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9
CHCl3), ee > 95%: 1H NMR (400 MHz, CDCl3)
2.05 (m, 6 H), 2.17 (bs, 3 H), 3.87 (d, J = 13.9 Hz, 1H), 3.94 (d, J = 13.9 Hz, 1H); 13C NMR (101 MHz, CDCl3)
Hz) 25.6, 25.8 (d, J = 1.5 Hz), 26.3 (d, J = 3.7 Hz), 26.5 (d, J = 3.7 Hz), 31.1 (3C), 35.6 (3C), 36.1 (d, J = 43.3 Hz), 43.9 (d, J = 2.93
Hz, 3C), 60.4 (d, J = 41.1 Hz), 81.3 (d, J = 6.6 Hz); 31P NMR (162 MHz, CDCl3) 109.3-111.2 (bm); 11B NMR (128 MHz, CDCl3)
δ
0.14-1.06 (m, 3 H), 1.14-1.47 (m, 5 H), 1.61 (bs, 6 H), 1.67-1.94 (m, 6 H), 1.94-
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δ
25.2 (d, J = 2.20
δ
δ
-40.3 (bd, J = 61.5 Hz); HRMS (ESI-MS) [M+Na]+: found 333.2126; calculated for C17H32BO2PNa+ 333.2128. Chiral HPLC: ana-
lytical separation on Chiralpak AS-H in heptane/isopropanol (95/5) at 1 ml/min and 25°C with UV detection at 220 nm
and polarimeter: Rt1 = 6.80 (−), Rt2 = 7.80 (+), k1 = 1.27 (−), k2 = 1.60 (+), α = 1.26, Rs = 2.02.
General procedure for the synthesis of hydroxymethylphosphine-boranes 8
To a solution of adamantyl(hydroxymethyl)phenyl-phosphine borane (0.28 mmol, 86 mg) in THF (3 mL) was added at
0°C the solution of RLi (3equiv). The resulting mixture was allowed to warm to room temperature and stirred further for
2h. The obtaining solution was subsequently quenched with water (2 mL), and then neutralized with the saturated NH4Cl
aqueous solution (5 mL). The product was extracted with CH2Cl2 (3 x 10 mL) and the combined organic layers were dried
over anhydrous Na2SO4. The solvents were removed under reduced pressure to give residue which was purified by silica
gel chromatography.
(Hydroxymethyl)methylphenylphosphine borane 8a. Hexane/AcOEt: 3/1 Rf = 0.4. Clear oil, 42 mg (88% yield) (RP)-(−)-
25
25
1
8a [α]D −9.3 (c = 1.2, CHCl3), ee = 97%; (SP)-(+)-8a [α]D +9.2 (c = 1.51, CHCl3), ee = 98%: H NMR (400 MHz, CDCl3)
δ
0.22-1.15 (m, 3H), 1.65 (d, J = 10.54 Hz, 3H), 2.1 (bs, 1H), 4.07 (s, 2H), 7.46-7.58 (m, 3H), 7.72-7.80 (m, 2H); 13C NMR (101
MHz, CDCl3)
δ 6.9 (d, J = 38.9 Hz), 61.05 (d, J = 41.1 Hz), 127.0 (d, J = 52.8 Hz, 1 C), 128.9 (d, J = 10.3 Hz, 2C), 131.8 (d, J = 2.2
31
11
Hz), 131.9 (d, J = 8.8 Hz, 2C); P NMR (162 MHz, CDCl3)
δ
10.05-11.61 (bm); B NMR (128 MHz, CDCl3) δ -41.1 (bd, J = 56.8
Hz); HRMS (ESI-MS) [M+Na]+: found 191.0773; calculated for C8H14BOPNa+ 191.0769. Chiral HPLC: analytical separation
on Chiralpak AD-H in hexane/ethanol (7/3) at 1 ml/min and 25°C with UV detection at 254 nm and polarimeter: Rt1 = 5.09
(RP)-(−), Rt2 = 7.03 (SP)-(+), k1 = 0.7 (RP)-(−), k2 = 1.34 (SP)-(+), α = 1.93, Rs = 5.29.
n-Butyl(hydroxymethyl)phenylphosphine borane 8b. Purification by column chromatography using CH2Cl2 as eluent
(Rf = 0.29). Clear oil, 64 mg (91% yield). (RP)-(−)-8b [α]D25 −18.4 (c = 0.8, CHCl3), ee = 97%; (SP)-(+)-8b [α]D25 +17.6 (c = 1.01,
1
CHCl3), ee = 98%: H NMR (400 MHz, CDCl3)
δ 0.23 – 1.10 (bm, 3H), 0.90 (t, J=7.02 Hz, 3H), 1.33 - 1.65 (m, 4H), 1.93 (bs,
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δ 13.5, 21.4 (d, J =
1H), 1.95 - 2.08 (m, 2H), 4.12 (s, 2 H), 7.45 - 7.59 (m, 3H), 7.72 - 7.81 (m, 2H); 13C NMR (101 MHz, CDCl3)
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4
5
35.2 Hz), 24.2 (d, J = 13.2 Hz), 24.7, 59.9 (d, J = 41.1 Hz), 126.2 (d, J = 52.08 Hz), 128.9 (d, J = 9.54 Hz, 2C), 131.7 (d, J=2.9 Hz),
132.3 (d, J = 8.07 Hz, 2C); 31P NMR (162 MHz, CDCl3) 15.7 - 17.5 (bm); 11B NMR (128 MHz, CDCl3)
-42.8 (bd, J = 59.2 Hz);
δ
δ
HRMS (ESI-MS) [M+Na]+: found 233.1241; calculated for C11H20BOPNa+ 233.1239. Chiral HPLC: analytical separation on
Chiralpak AZ-H in heptane/ethanol (8/2) at 1 ml/min and 25°C with UV detection at 254 nm and polarimetric: Rt1 = 4.64
(RP)-(−), Rt2 = 5.24 (SP)-(+), k1 = 0.55 (RP)-(−), k2 = 0.75 (SP)-(+), α = 1.36, Rs = 2.04.
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Oxidative One-Carbon Degradation of (adamantyl)(t-butyl)(hydroxymethyl)phosphinite-borane
Adamantylhydrogeno-t-butylphosphinite-borane 9. To a solution of KOH (2.2 mmol, 10 equiv., 128 mg) and K2S2O8
(0.66 mmol, 3 equiv., 185 mg) in water (2.0 mL) was added the solution of RuCl3.xH2O (10 mg, 20-30% molar) in water (1
mL) at 0°C. The resulting mixture was allowed to be stirred at 0°C for 20 min and then the solution of (adaman-
tyl)(hydroxymethyl)(t-butyl)phosphinite-borane (0.22 mmol, 0.065g) in acetonitrile (1 mL) was slowly added. The reac-
tion solution was allowed to be further stirred for 10h at RT. The obtaining solution was diluted with water and neutral-
ized with HCl aqueous solution (2M). The product was extracted with CH2Cl2 (3 x 10 mL) and the combined organic layers
were dried over Na2SO4. The solvents were removed under reduced pressure to give residue which was purified by silica
1
gel chromatography using CH2Cl2/petroleum ether (1/9) as eluent (RF = 0.17). Solid 48 mg, 83% yield. H NMR (400 MHz,
CDCl3)
δ 0.20 - 1.05 (m, 3H), 1.18 (d, J = 15.22 Hz, 9H), 1.63 (bs, 6H), 1.99 (bs, 6H), 2.20 (bs, 3H), 6.20 (d, J = 355.47 Hz, 1H);
13C NMR (101 MHz, CDCl3)
δ
24.9 (d, J = 2.93 Hz), 30.0 (d, J = 45.48 Hz), 31.1 (3C), 35.7 (3C), 43.2 (d, J = 3.67 Hz, 3C), 80.3
31
11
(d, J = 8.8 Hz); P NMR (162 MHz, CDCl3)
δ
102.7-104.2 (bm); B NMR (128 MHz, CDCl3)
δ
-39.7 (bd, J=60.0 Hz); HRMS
(ESI-MS) [M+Na]+: found 277.1866; calculated for C14H28BOPNa+ 277.1866.
Alkylation of secondary phosphinite-borane
Adamantylbenzyl-t-butylphosphinite-borane 10. To a solution of (adamantyl)hydrogeno-t-butylphosphinite-borane
(0.22 mmol, 0.055g) in THF (2mL) was added slowly at -78°C the solution of n-BuLi (1.6M in n-hexane) (0.33 mmol, 1.5
equiv., 0.2mL). The mixture was stirred for 20 min while maintaining the reaction temperature at -78°C. Benzyl bromide
(0.88 mmol, 4 equiv., 0.102 mL) was added and the obtaining solution was maintained at -78°C for further 2h and then
was allowed to warm to 0°C during 2h. The reaction was quenched with the saturated NH4Cl aqueous solution. The prod-
uct was extracted with CH2Cl2 (3 x 10 mL) and the combined organic layers were dried over anhydrous Na2SO4. The sol-
vents were removed under reduced pressure to give oily residue which was purified by column chromatography on silica
gel with CH2Cl2/petroleum ether in ratio of 1:9 as eluent (Rf = 0.13). White solid, 72 mg, 97% yield. (SP)-(−)-10 [α]D25 −36.2
25
1
(c = 0.97, CHCl3), ee = 95%; (RP)-(+)-10 [α]D +37.6 (c = 0.95, CHCl3), ee = 95%: H NMR (400 MHz, CDCl3)
δ 0.31 – 1.12
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(bm, 3H), 1.18 (d, J = 13.80 Hz, 9H), 1.44 - 1.54 (m, 6H), 1.55 - 1.62 (m, 3H), 1.79 (bd, J = 11.04 Hz, 3H), 2.02 (bs, 3H), 3.01 (d, J
= 13.60 Hz, 1H), 3.15 (t, J = 13.60 Hz, 1H), 7.21 - 7.35 (m, 5H); 13C NMR (101 MHz, CDCl3)
24.8 (d, J = 2.93 Hz), 31.2 (3C), 32.8
(d, J = 44.0 Hz), 34.7 (d, J = 31.5 Hz), 35.7 (3C), 43.6 (d, J = 2.93 Hz, 3C), 81.5 (d, J = 7.3 Hz), 126.6 (d, J = 2.9 Hz) 128.0 (d, J =
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δ
4
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6
7
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2.20 Hz, 2C), 130.9 (d, J = 4.40 Hz, 2C), 133.22 (d, J = 7.34 Hz); P NMR (162 MHz, CDCl3)
δ 118.14 - 119.89 (bm); B NMR
-39.41 (bd, J = 60.7 Hz); HRMS (ESI-MS) [M+NH4]+: found 362.2785; calculated for C21H38BNOP+
8
9
(128 MHz, CDCl3)
δ
10
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362.2783. Chiral HPLC: analytical separation on Chiralcel OD-3 in heptane/isopropanol (95/5) at 1 ml/min and 25°C with
UV detection at 220 nm and polarimeter: Rt1 = 4.01 (SP)-(−), Rt2 = 5.16 (RP)-(+), k1 = 0.34 (SP)-(−), k2 = 0.72 (RP)-(+), α = 2.13,
Rs = 3.4.
ASSOCIATED CONTENT
Supporting information: the crystal structure of (+)-(RP)-3e; (-)-(RP)-6a; (+)-(RP)-6c; (-)-(SP)-7c and (+)-(RP)-10, NMR spectra of
all new compounds and HPLC data for the determination of enantiomeric excesses. This material is available free of charge via
the Internet at http://pubs.acs.org/.
AUTHOR INFORMATION
Corresponding Author
* (laurent.giordano@centrale-marseille.fr, julien.leclaire@univ-lyon1.fr)
Present Addresses
† Université Claude Bernard, CNRS, ICBMS UMR 5246, 69622, Villeurbanne, France.
ACKNOWLEDGMENT
We are grateful to the CNRS, Centrale Marseille and Aix-Marseille University for funding. We thank Marion Jean for HPLC
analyses, Dr. Michel Giorgi for X-ray analyses, Dr. Valerie Monnier and Christophe Chendo for HRMS analyses.
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7 Hérault, D.; Buono, G.; Vanthuyne, N.; Roussel, C.; Giordano, L.; Moraleda, D.; Gatineau, D.; Leclaire, J.; Nuel, D. P-stereogenic chi-
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11 Geoffrey B. Cox in Preparative Enantioselective Chromatography John Wiley & Sons, 2008
12 No trace of the desired compound was observed using our conditions.
13 Georgiadis, D.; Matziari, M.; Vassiliou, S.; Dive, V.; Yiotakis, A. Tetrahedron 1999, 55, 14635.
14 The sign given for the enantiomers is the sign of the specific rotation at 25°C at 589 nm in chloroform.
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15 The absolute configurations of compounds (RP)-(+)-3a and (SP)-(-)-3a were deducted on the basis of our previous work see ref 8b
and Wang, F.; Polavarapu, P. L.; Drabowicz, J.; Mikolajczyk, M. J. Org. Chem. 2000, 65, 7561. The absolute configuration of (+)-(RP)-3e; (-
)-(RP)-6a; (+)-(RP)-6c; (-)-(SP)-7c and (+)-(RP)-10 were secured by X-ray structure CCDC 1048712-1048716.
16 Shaikh, T. M.; Weng, C.-M.; Hong, F.-E. Coord. Chem. Rev. 2012, 256, 771.
1
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8
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17 Deprotonation of (RP)-(+)-3i (de > 99%) at −78 °C with lithium diisopropylamide followed by addition of 1 equiv of sodium menth-
ylate lead, after 2 hours at this temperature and hydrolysis, to 3i with only 68% diastereomeric excess (See experimental section for de-
tail).
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20 Hérault, D.; Nguyen, D.-H.; Nuel, D.; Buono, G. Chem. Soc. Rev., 2015, DOI: 10.1039/c4cs00311j.
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22 See supporting information table S1.
23 Sowa, S.; Stankevič, M.; Szmigielska, A.; Małuszyńska, H.; Kozioł, A. E.; Pietrusiewicz, K. M. J. Org. Chem. 2015, 80, 1672.
24 (a) ref 22; (b) Granander, J.; Secci, F.; Canipa, S. J.; O'Brien, P.; Kelly, B. J. Org. Chem. 2011, 76, 4794; (c) Johansson, M. J.; Berglund,
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KGaA, Weinheim, 2008, pp. 1211.
26 The substitution of phosphinite-borane with bulky organolithium reagents was only reported Brown and coworker: Brown, J. M.;
Laing, J. C. P. J. Organomet. Chem. 1997, 52I9, 435.
27 Nagata, K.; Matsukawa, S.; Imamoto, T. J. Org. Chem. 2000, 65, 4185.
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29 Shioji, K.; Kurauchi, Y.; Okuma, K. Bull. Chem. Soc. Jpn. 2003, 76, 833.
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