Asymmetric synthesis of SMS-Phos series' precursor and a naphthalene analogue

Article abstract of DOI:10.1016/j.tetlet.2010.12.106

An efficient and high-yielding (up to 57% overall yield) asymmetric route to enantiopure P-stereogenic 1,2-bis[(o-hydroxyaryl)(phenyl)phosphino-P-borane] ethanes wherein aryl = phenyl and naphthyl, is presented. The occurring P-stereomutation is confirmed

Full text of DOI:10.1016/j.tetlet.2010.12.106

Tetrahedron Letters 52 (2011) 1086–1089
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric synthesis of SMS-Phos series’ precursor and a naphthalene
analogue
Michel Stephan a,b,c, , Barbara Modec d, Barbara Mohar a,b,
⇑
⇑
a EN?FIST Centre of Excellence, Dunajska 156, SI-1000 Ljubljana, Slovenia
b Laboratory of Organic and Medicinal Chemistry, National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia
c PhosPhoenix SARL, 115, rue de l’Abbé Groult, F-75015 Paris, France
d
ˇ
Department of Chemistry and Chemical Technology, University of Ljubljana, Aškerceva 5, SI-1001 Ljubljana, Slovenia
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and high-yielding (up to 57% overall yield) asymmetric route to enantiopure P-stereogenic
1,2-bis[(o-hydroxyaryl)(phenyl)phosphino-P-borane]ethanes wherein aryl = phenyl and naphthyl, is pre-
sented. The occurring P-stereomutation is confirmed through X-ray crystal structure analysis of key
intermediates.
Received 22 November 2010
Revised 10 December 2010
Accepted 20 December 2010
Available online 7 January 2011
Ó 2011 Published by Elsevier Ltd.
Keywords:
Asymmetric synthesis
Absolute configuration
P ligands
Highly sought in transition metal-catalyzed asymmetric trans-
formations by the fine chemical industry and research laboratories
alike, phosphine ligands are the key component of many catalysts
conveying the embedded chiral information to the end product.1
Following Knowles and co-workers’ historical design of the iconic
P-stereogenic 1,2-bis[(o-anisyl)(phenyl)phosphino]ethane (DiP-
genic ethane-bridged diphosphine series with markedly
enhanced efficiency.4 The upgradeable feature of the P-o-hydroxy-
aryl groups, for example, through alkylation or esterification of the
hydroxy functionality, followed by P-borane removal, permits the
preparation with ease of a large series of homochiral diphosphines.
The basic diphosphine structure wherein the o-hydroxyaryl repre-
sents an o-hydroxyphenyl group has been dubbed ‘SMS-Phos’.
Our outlined strategy is a modified Jugé–Stephan approach call-
ing upon C,O-double-metal o-lithio-aroxides in place of regular and
more common uni-metal organolithiums (Scheme 1).5 Hence, the
P–O bond cleavage by o-Li-ArOM (M = Li or Na) reagents (step i)
followed by the acid-catalyzed P–N bond methanolysis to a P–
OMe bond (step ii), and further displacement of the resulting P-
OMe group with MeLi (step iii), furnished the (o-hydroxy-
aryl)(methyl)(phenyl)phosphine-P-borane (3) intermediates. Sub-
AMP) ligand and its application in the L
-DOPA process,2 alternative
synthetic methodologies toward P-stereogenic ethane-bridged
diphosphines were devised by others.3 Of particular interest, a very
flexible and high-yielding access to a diversified array of enantio-
pure phosphorus-based compounds in either enantiomeric form,
is the widely-applied Jugé–Stephan asymmetric route.3b–d It relies
upon the regio- and stereoselective two-step sequential displace-
ment of (+)- or (ꢀ)-ephedrine auxiliary from an enantiopure
1,3,2-oxazaphospholidine-2-borane complex.
sequently, the Cu(II)-catalyzed oxidative homocoupling of the
a-
lithiated derivatives promoted the formation of 1,2-bis[(o-
hydroxyaryl)(phenyl)phosphino-P-borane]ethane (4) precursors
of SMS-Phos and its analogues. Advantageously, this approach of-
fers the option to functionalize the aromatic hydroxy groups at
any stage of the synthesis. This is illustrated hereafter by convert-
ing the P-o-hydroxyaryl groups into the corresponding P-o-
methoxyaryls and comparison with the P-o-methoxyaryl-contain-
ing analogous products6 prepared via the Jugé–Stephan route.
DiPAMP was first prepared via Mislow’s method2a,7 then Imam-
oto’s3a,8 recoursing to diastereomeric separation of P-stereogenic l-
menthyl phosphinates and l-menthyl phosphinite-P-boranes,
respectively. Notably, the facile decomplexation of phosphine-P-
RO
OR
R = Me : (R,R)-DiPAMP
(R,R)-SMS-Phos
P
P
H
:
Ph
Ph
In our cumulative research efforts on metal-phosphines, we
present herein our synthetic route toward 1,2-bis[(o-hydroxy-
aryl)(phenyl)phosphino-P-borane]ethane precursors of P-stereo-
⇑
Corresponding authors. Tel.: +386 1 4760250; fax: +386 1 4760300.
E-mail addresses: mstephan@phosphoenix.com (M. Stephan), barbara.mohar@-
ki.si (B. Mohar).
0040-4039/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.12.106

M. Stephan et al. / Tetrahedron Letters 52 (2011) 1086–1089
1087
corresponding (+)-[(1S,2R)-N-ephedrino](1-methoxy-2-naphthyl)-
(phenyl)phosphine-P-borane (1b0) displaying identical spectral
BH
P
BH
P
3
3
HO
Ph
Me
Ph
characteristics and optical rotation (½a D25
ꢂ
= +1.8 (c 1.0, CHCl3)) as
(i)
O
N
Ar
Ph
N
Me
the reference compound.14 Single diastereomers 1a,b (100% de)
were exclusively detected by 1H NMR, which were readily iso-
lated with 92% yield as stable and highly crystalline products.
The X-ray crystal diffraction analyses of 1a (Fig. 1)15a and 1b
(Fig. 2)15b revealed (RP)-configurations confirming the retention
of P-configuration ensuing this transformation. Interestingly, two
crystallographically independent molecules were observed in the
asymmetric unit of 1a. The two molecules are noticeably distin-
guishable by the different mutual orientation of the P-o-hydroxy-
phenyl groups (Supplementary data, Fig. S2). The hydroxy groups
in 1a are engaged in relatively strong intermolecular H-bonding
interactions with OꢁꢁꢁO = 2.801(3) and 2.860(2) Å.16
Ph
Me
Me
100% de
(2S,4R,5S)-( )-OxazaPB
(derived from (+)-ephedrine)
1a,b
(v)
1a',b'
BH
3
BH
P
3
(iii)
(ii)
P
Ar
(v)
Me
Ar
MeO
Ph
Ph
100% ee
100% ee
3a,b
2a,b
(v)
3a',b'
2a',b'
The H2SO4 (1 equiv) methanolysis of the (RP)-aminophosphine-
P-borane 1a (step ii) and successive etherification with MeI (step
v), furnished the anticipated methyl (+)-(o-anisyl)(phenyl)phosph-
BH
3
inite-P-borane (2a0) (½a D25
ꢂ
= +26.7 (c 1.0, CHCl3)).17 In turn, the
(iv)
P
P
naphthalene analogue (RP)-1b provided (+)-2b0 (½a D25
ꢂ
= +5.6 (c 1.0,
Ar
Ar
CH
CH
2
− BH
2
3
2
2
CHCl3)).18 Moreover, the methanolysis of (RP)-1a using BF3ꢁEt2O
or BF3ꢁMeOH (ꢃ1 equiv) afforded 2a with identical optical rota-
Ph
Ph
100% ee
(R,R)-
100% ee
4a,b
tions as obtained via protomethanolysis with H2SO4 (½a D25
ꢂ
= +23.6
(v)
Ar = o-HO-Ph: SMS-Phos
o-RO-Ph: R-SMS-Phos
4a',b'
(c 1.0, abs MeOH)). The pivotal crystalline synthons methyl phos-
phinite-P-boranes 2a,b were isolated with 95–96% yield, and were
virtually enantiomerically pure as determined by HPLC analysis on
ChiralcelÒ OJ (hexane/2-PrOH 70:30). The X-ray diffraction analy-
sis of the (S)-Mosher’s ester of (+)-2a revealed an (SP)-configuration
(Fig. 3).19
RO
RO
Ar
R
H
a
b
Me
a'
b'
What preceded unambiguously proves that the methanolysis of
(RP)-[(1S,2R)-N-ephedrino](o-hydroxyphenyl)(phenyl)phosphine-
P-borane (1a), and by extension of 1b, proceeds with inversion of
P-configuration, and consequently validates the previously sug-
gested inversion of P-configuration occurring during the methanol-
ysis of their 2-methoxyarene analogues (RP)-1a0,b0 (Jugé–Stephan
route).
Scheme 1. Reagents and conditions: (i) o-Li-ArOM (M = Li or Na), THF, ꢀ20 °C to rt
(92% yield); (ii) MeOH, H2SO4 (or MeOH, BF3ꢁEt2O), rt (95–96% yield); (iii) MeLi
(>2 equiv), or NaH (>1 equiv) followed by MeLi (>1 equiv), THF, ꢀ20 °C to rt
(92ꢀ94% yield); (iv) s-BuLi (2 equiv), or NaH (>1 equiv) followed by s-BuLi (1 equiv),
THF, ꢀ30 °C then CuCl2, ꢀ30 °C (70% yield); (v) MeI, K2CO3, acetone, 50 °C (95–98%
yield).
Further on, the displacement of the P-OMe group with MeLi
from methyl (SP)-(+)-(o-hydroxyphenyl)(phenyl)phosphinite-P-
borane (2a) (step iii) followed by etherification with MeI (step v),
resulted in the formation of (RP)-(ꢀ)-PAMPꢁBH3 (3a0)
boranes under mild conditions with full retention of P-configura-
tion was demonstrated by Imamoto et al.8 Independently, several
Rh–DiPAMP complexes have been characterized by X-ray crystal
diffraction revealing DiPAMP’s absolute configuration.2a,9
(½a 2D5
= ꢀ26.1 (c 1.3, abs MeOH) in practically enantiopure form
ꢂ
as determined by HPLC analysis on ChiralcelÒ OK (hexane/EtOH
According to the later developed Jugé–Stephan route toward
DiPAMP,3b–d the retention of P-configuration during the formation
of (o-anisyl)(N-ephedrino)(phenyl)phosphine-P-borane (1a0) by
ring-opening of the 1,3,2-oxazaphospholidine-2-borane complex10
(oxazaPB) with o-Li-PhOMe, has been established by X-ray crystal-
lography.11 However, the successive inversions of P-configuration
resulting from the P–N bond methanolysis and the displacement
of the P-OMe group with MeLi giving rise to (o-anisyl)(methyl)-
(phenyl)phosphine-P-borane (PAMPꢁBH3, 3a0) intermediate of
known P-configuration,3a,8 have been proposed3b by analogy with
the chemistry of l-menthyl phosphinite-P-boranes8 and extrapola-
tion of the stereochemistry encountered in the P-oxide series.12
Nevertheless, to ensure well-defined intermediates, the P-stereo-
chemistry occurring at the different stages of our strategy toward
SMS-Phos and a naphthalene analogue was scrutinized and the
suggested one during the Jugé–Stephan route was inspected.
Thus, the ring-opening of enantiopure (2S,4R,5S)-(ꢀ)-oxazaPB
derived from (1S,2R)-(+)-ephedrine with lithium o-lithio-phenox-
ide13 (step i) followed by regioselective etherification with MeI
(step v), led to (RP)-(ꢀ)-(o-anisyl)[(1S,2R)-N-ephedrino](phenyl)-
phosphine-P-borane (1a0) as indicated by 1H and 13C NMR analyses,
80:20).20 Likewise, the naphthalene analogue (ꢀ)-2b gave (+)-3b0
(½a 2D5
ꢂ
= +68.5 (c 1.0, CHCl3)).21 The analysis of the acquired data
for the known (RP)-(ꢀ)-PAMPꢁBH3 (3a0) shows the inversion of P-
configuration during the formation of its related (RP)-(+)-(o-
hydroxyphenyl)(methyl)(phenyl)phosphine-P-borane (3a) from
and optical rotation (½a D25
ꢂ
= ꢀ34.7 (c 1.0, CHCl3), ½a D25
= ꢀ38.4 (c 1.0,
ꢂ
CH2Cl2)) comparison with the reference compound.11 Analogously,
the reaction with lithium 2-lithio-1-naphthoxide (step i) followed
by selective mono-O-alkylation with MeI (step v), led to the
Figure 1. ORTEP drawing of (RP)-1a at the 30% probability level. A single molecule
belonging to the asymmetric unit is only shown.

1088
M. Stephan et al. / Tetrahedron Letters 52 (2011) 1086–1089
feature of the free phenolic group can be conveniently exploited
to advantage for further optimal elaboration of the intermediates
and broadening their scope. Progress in this area will be communi-
cated in due course.
Acknowledgments
This work was supported by the Ministry of Higher Education,
Science, and Technology of the Republic of Slovenia (Grant No.
P1-242). M.S. acknowledges the innovation stimulation (No.
00P141 to PhosPhoenix SARL) by the Ministry of National Educa-
tion, Research, and Technology of France. We thank Damjan Šterk
for preparing the Mosher’s ester of 2a and helping in analysis.
Figure 2. ORTEP drawing of (RP)-1b at the 30% probability level.
Supplementary data
Supplementary data (experimental procedures for the prepara-
tion of all new compounds and X-ray structure determination of
1a, 1b, and Mosher’s ester of 2a) associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2010.12.106.
References and notes
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Figure 3. ORTEP drawing of the (S)-Mosher’s ester of (+)-2a at the 30% probability
level.
3. For leading references, see: (a) Imamoto, T.; Oshiki, T.; Onozawa, T.; Kusumoto,
T.; Sato, K. J. Am. Chem. Soc. 1990, 112, 5244–5252; (b) Jugé, S.; Stephan, M.;
Laffitte, J. A.; Genêt, J.-P. Tetrahedron Lett. 1990, 31, 6357–6360; (c) Jugé, S.;
Genêt, J.-P. WO9100286, 1991; (d) Laffitte, J. A.; Jugé, S.; Genêt, J.-P.; Stephan,
M. FR2672603, 1991; WO9214739, 1992; (e) Corey, E. J.; Zhuoliang, C.;
Tanoury, G. J. J. Am. Chem. Soc. 1993, 115, 11000–11001; (f) Muci, A. R.; Campos,
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Kikuchi, S.; Yasutake, M.; Imamoto, T. Eur. J. Org. Chem. 2002, 15, 2535–2546.
4. (a) Stephan, M.; Mohar, B. FR2887253, 2005; WO2006136695, 2006; (b)
methyl (SP)-(o-hydroxyphenyl)(phenyl)phosphinite-P-borane (2a).
By extension, an identical (RP)-stereochemistry outcome for the
naphthalene counterpart 3b can be attributed. The (o-hydroxy-
aryl)(methyl)(phenyl)phosphine-P-boranes 3a,b were isolated in
crystalline form with 92–94% yield.
Finally, the Cu(II)-catalyzed oxidative homocoupling of the pre-
formed a-lithio anions of (RP)-3a,b (step iv), led exclusively to the
ˇ ˇ
Zupancic, B.; Mohar, B.; Stephan, M. Adv. Synth. Catal. 2008, 350, 2024–2032; (c)
Stephan, M.; Šterk, D.; Mohar, B. Adv. Synth. Catal. 2009, 351, 2779–2786; (d)
ˇ ˇ
Zupancic, B.; Mohar, B.; Stephan, M. Tetrahedron Lett. 2009, 50, 7382–7384; (e)
crystalline ethane-bridged diphosphine-P-boranes (RP,RP)-4a
Zupancˇicˇ, B.; Mohar, B.; Stephan, M. Org. Lett. 2010, 12, 1296–1299; (f)
(½a 2D5
ꢂ
= +26.6 (c 1.0, abs MeOH)) and (RP,RP)-4b (½a D25
ꢀ7.5 (c 1.2,
ꢂ
ˇ ˇ
Zupancic, B.; Mohar, B.; Stephan, M. Org. Lett. 2010, 12, 3022–3025.
CHCl3)) as single diastereomers (100% de as evidenced by 1H and
31P NMR) with 70% isolated yields. These results ascertain the high
enantiomeric purities of the starting (RP)-3a,b. Their etherification
with MeI (step v) furnished the corresponding known crystalline
5. P-stereogenic (o-hydroxyaryl)(methyl)(phenyl)phosphines with 72–91% ee
were prepared through Fries rearrangement of the corresponding 2-(1-
bromoaryl) phosphinite-P-boranes. For this, see: Moulin, D.; Bago, S.;
Bauduin, C.; Darcel, C.; Jugé, S. Tetrahedron: Asymmetry 2000, 11, 3939–3956.
6. For P-o-anisyl derivatives, see Ref. 3b, and for P-(1-methoxy-2-naphthyl)
derivatives, see Ref. 4b.
7. (a) Korpiun, O.; Lewis, R. A.; Chickos, J.; Mislow, K. J. Am. Chem. Soc. 1968, 90,
4842–4846; (b) Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J. J. Mol. Catal.
1983, 19, 159–169.
methoxyarenes (RP,RP)-4a0 and (RP,RP)-4b0.23 Similarly to the lat-
22
ter transformation, various functionalizations of the hydroxy
groups of 4a,b can be performed generating a very large series of
P-borane-protected diphosphines which by simple decomplex-
ation (e.g., 55–60 °C in Et2NH) furnish the corresponding homochi-
ral diphosphine ligands.24 Noteworthy, both (R,R)- and (S,S)-
enantiomers of the borane-free diphosphine were prepared start-
ing from (2S,4R,5S)-oxazaPB and its (2R,4S,5R)-enantiomer,
respectively.
In summary, we have detailed the expedient and efficient asym-
metric synthesis of enantiopure SMS-Phos series’ precursor and a
close naphthalene analogue in preparatively good overall yields.
As a corollary, the aminophosphine-P-borane methanolysis–P-
methoxy group displacement intermediate sequence was con-
firmed to proceed with successive inversions of P-configuration.
The highly crystalline nature of the obtained P-o-hydroxyaryl-con-
taining compounds facilitates isolation, storage without any special
precaution, and easy handling. In all respects, the upgradeable
8. Imamoto, T.; Kusumoto, T.; Suzuki, N.; Sato, K. J. Am. Chem. Soc. 1985, 107,
5301–5303.
9. (a) McCulloch, B.; Halpern, J.; Thompson, M. R.; Landis, C. R. Organometallics
1990, 9, 1392–1395; (b) Giovannetti, J. S.; Kelly, C. M.; Landis, C. R. J. Am. Chem.
Soc. 1993, 115, 4040–4057; (c) Drexler, H.-J.; Zhang, S.; Sun, A.; Spannenberg,
A.; Arrieta, A.; Preetz, A.; Heller, D. Tetrahedron: Asymmetry 2004, 15, 2139–
2150; (d) Schmidt, T.; Baumann, W.; Drexler, H.-J.; Arrieta, A.; Heller, D.
Organometallics 2005, 24, 3842–3848.
10. For X-ray crystal structure of (2R,4S,5R)-(+)-oxazaPB, see: Jugé, S.; Stephan, M.;
Genêt, J.-P.; Halut-Desportes, S.; Jeannin, S. Acta Crystallogr., Sect. C 1990, 46,
1869–1872.
11. The ring-opening of (2S,4R,5S)-(ꢀ)-oxazaPB derived from (1S,2R)-(+)-
ephedrine with o-anisyllithium led to (RP)-(ꢀ)-1a0 with retention of P-
configuration (100% de, [a]D = ꢀ38.3 (c 1, CH2Cl2), mp 111 °C). For this, see:
Jugé, S.; Stephan, M.; Merdès, R.; Genêt, J.-P.; Halut-Desportes, S. J. Chem. Soc.,
Chem. Commun. 1993, 531–533. For its (SP)-(+)-enantiomer, see Ref. 3b.
12. (a) Koizumi, T.; Yanada, R.; Takagi, H.; Hirai, H.; Yoshii, E. Tetrahedron Lett.
1981, 22, 477–480; (b) Koizumi, T.; Yanada, R.; Takagi, H.; Hirai, H.; Yoshii, E.
Tetrahedron Lett. 1981, 22, 571–572; (c) Jugé, S.; Genêt, J.-P. Tetrahedron Lett.
1989, 30, 2787–2790.

M. Stephan et al. / Tetrahedron Letters 52 (2011) 1086–1089
1089
13. For generation of o-LiOPhLi, see: (a) Talley, J. J.; Evans, I. A. J. Org. Chem. 1984,
49, 5267–5269; For detailed study of ring-opening of oxazaPB, see: (b) Stephan,
M. M. S.; Šterk, D.; Modec, B.; Mohar, B. J. Org. Chem. 2007, 72, 8010–8018.
14. The ring-opening of (2S,4R,5S)-(ꢀ)-oxazaPB derived from (1S,2R)-(+)-
ephedrine with 1-methoxy-2-naphthyllithium led to (+)-1b0 (100% de,
molecule of 1a with the same orientation forms less H-bonds than the
molecule with the other orientation.
17. The H2SO4 catalyzed methanolysis of (SP)-1a0 derived from (1R,2S)-(ꢀ)-
ephedrine led to (ꢀ)-2a0 (>98% ee, [
a]D = ꢀ26.3 (c 1.0, CHCl3)). For this, see
Ref. 3b.
½
a 2D5
ꢂ
= +1.8 (c 1.0, CHCl3)). For this, see Ref. 4b.
18. The H2SO4 catalyzed methanolysis of (+)-1b0 derived from (1S,2R)-(+)-
15. Crystallographic data (excluding structure factors) of the structures associated
with this article have been deposited at the Cambridge Crystallographic Data
Centre. Copies of the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 1223336033; e-mail:
deposit@ccdc.cam.ac.uk). (a) Crystal data for 1a: CCDC-791281. (b) Crystal data
for 1b: CCDC-791282.
ephedrine led to (+)-2b0 (½a D25
ꢂ
= +5.6 (c 1.0, CHCl3)). For this, see Ref. 4b.
19. Crystal data for (S)-Mosher’s ester of (+)-2a: CCDC-791283.
20. For (RP)-(ꢀ)-3a0 (>98% ee) with ½a 2D5
= ꢀ26.0 (c 1.3, MeOH), see Ref. 3b, and for
ꢂ
(SP)-(+)-3a0 (89% ee) with ½a 2D5
ꢂ
= +24.1 (c 1.5, MeOH), see Refs. 3a and 8.
21. The displacement of the P-OMe of (+)-2b0 by MeLi led to (+)-3b0 with
½ ꢂ = +68.5 (c 1.0, CHCl3). For this, see Ref. 4b.
a 2D5
16. No short interactions of this type were observed for the counterpart 1b. The
single orientation of the 1-hydroxy-2-naphthyl group in 1b matches exactly
one of the two orientations of the o-hydroxyphenyl group in 1a
(Supplementary data, Fig. S5). The disposition of the OH groups in 1b does
not seem to favor the establishment of an intermolecular H-bond. Indeed, the
22. For (RP,RP)-4a0 (100% ee, ½a D25
ꢂ
= +66 (c 1.3, CHCl3)), see Ref. 3b, and for its
ꢂ
(SP,SP)-enantiomer (100% ee, ½a D25
= ꢀ70.2 (c 1.3, CHCl3)), see Refs. 3a and 8.
23. For (RP,RP)-4b0 (100% ee, ½a D25
ꢂ
= +122.2 (c 1.0, CHCl3)), see Ref. 4b.
ˇ ˇ
24. Stephan, M.; Šterk, D.; Zupancic, B.; Mohar, B., in preparation.