Enantioselective synthesis of P-stereogenic benzophospholanes via palladium-catalyzed intramolecular cyclization

Article abstract of DOI:10.1021/ol0700512

(Chemical Equation Presented) Enantioselective or diastereoselective intramolecular cyclization of functionalized secondary phosphines or their borane adducts catalyzed by chiral Pd(diphosphine) complexes gave P-stereogenic benzophospholanes in up to 70%

Full text of DOI:10.1021/ol0700512

ORGANIC
LETTERS
2007
Vol. 9, No. 6
1109-1112
Enantioselective Synthesis of
P-Stereogenic Benzophospholanes via
Palladium-Catalyzed Intramolecular
Cyclization
Tim J. Brunker,† Brian J. Anderson,† Natalia F. Blank,† David S. Glueck,*,† and
Arnold L. Rheingold‡
6128 Burke Laboratory, Department of Chemistry, Dartmouth College, HanoVer, New
Hampshire, 03755, and Department of Chemistry, UniVersity of California, San Diego,
La Jolla, California, 92093
glueck@dartmouth.edu
Received January 8, 2007
ABSTRACT
Enantioselective or diastereoselective intramolecular cyclization of functionalized secondary phosphines or their borane adducts catalyzed by
chiral Pd(diphosphine) complexes gave P-stereogenic benzophospholanes in up to 70% ee. These results provide a new method for the
synthesis of chiral phospholanes, which are valuable ligands in asymmetric catalysis.
Chiral phospholanes such as Me-DuPhos (1) and Me-BPE
(2) are outstanding ligands for catalytic asymmetric hydro-
genation.1 The success of these phosphines has encouraged
the synthesis and application of a wide variety of analogues
with chiral carbon centers on the phospholane rings.2 More
recently, related useful P-stereogenic phospholanes such as
TangPhos (3),3 ligand 4,4 i-Pr-BeePhos (5),5 and phosphabi-
cyclooctane (PBO) acylation catalyst 66 have been prepared
in industrial and academic labs (Figure 1).
Because of the lack of general synthetic routes to P-
stereogenic phosphines,7 such ligands remain relatively
uninvestigated. For this reason, “not only are P-chirogenic
1,2-bisphospholanes interesting from a practical standpoint
(i.e., their use in catalysis), but they also represent a worthy
synthetic challenge”.4 Here, we report a new method for
enantioselective synthesis of P-stereogenic benzophos-
pholanes via Pd-catalyzed intramolecular8 asymmetric phos-
phination.9 Imamoto has prepared related benzophospholanes
† Dartmouth College.
‡ University of California.
(1) Burk, M. J. Acc. Chem. Res. 2000, 33, 363-372.
(2) For reviews, see: (a) Tang, W.; Zhang, X. Chem. ReV. 2003, 103,
3029-3070. (b) Clark, T.; Landis, C. Tetrahedron: Asymmetry 2004, 15,
2123-2137. For some recent examples, see: (c) Dubrovina, N. V.; Jiao,
H.; Tararov, V. I.; Spannenberg, A.; Kadyrov, R.; Monsees, A.; Christiansen,
A.; Borner, A. Eur. J. Org. Chem. 2006, 3412-3420. (d) Holz, J.; Zayas,
O.; Jiao, H.; Baumann, W.; Spannenberg, A.; Monsees, A.; Riermeier, T.
H.; Almena, J.; Kadyrov, R.; Borner, A. Chem.-Eur. J. 2006, 12, 5001-
5013. (e) Bilenko, V.; Spannenberg, A.; Baumann, W.; Komarov, I.; Borner,
A. Tetrahedron: Asymmetry 2006, 17, 2082-2087. (f) Berens, U.; Englert,
U.; Geyser, S.; Runsink, J.; Salzer, A. Eur. J. Org. Chem. 2006, 2100-
2109. (g) Liu, D.; Zhang, X. Eur. J. Org. Chem. 2005, 646-649.
(3) Tang, W.; Zhang, X. Angew. Chem., Int. Ed. 2002, 41, 1612-1614.
(4) Hoge, G. J. Am. Chem. Soc. 2003, 125, 10219-10227.
(5) Shimizu, H.; Saito, T.; Kumobayashi, H. AdV. Synth. Catal. 2003,
345, 185-189.
(6) Vedejs, E.; Daugulis, O. J. Am. Chem. Soc. 2003, 125, 4166-4173.
(7) (a) Grabulosa, A.; Granell, J.; Muller, G. Coord. Chem. ReV. 2007,
251, 25-90. (b) Johansson, M. J.; Kann, N. C. Mini-ReV. Org. Chem. 2004,
1, 233-247.
(8) For related intramolecular cyclizations in Pd-catalyzed amination,
see: (a) Wagaw, S.; Rennels, R. A.; Buchwald, S. L. J. Am. Chem. Soc.
1997, 119, 8451-8458. (b) Kitagawa, O.; Yoshikawa, M.; Tanabe, H.;
Morita, T.; Takahashi, M.; Dobashi, Y.; Taguchi, T. J. Am. Chem. Soc.
2006, 128, 12923-12931.
10.1021/ol0700512 CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/14/2007

chiral catalyst precursor Pd(diphos*)(trans-stilbene) gave
benzophospholanes 10a-c (Scheme 2, Table 1).13
Scheme 2. Pd-Catalyzed Intramolecular Phosphinationa
a The catalyst precursor ([Pd*]) was Pd(diphos*)(trans-stilbene).
See Table 1 for diphos* ligands, whose structures are included in
the Supporting Information (SI).
Table 1. Asymmetric Synthesis of Benzophospholanes via
Pd-Catalyzed Intramolecular Phosphinationa
yield
(%)
ee
(%)
entry
ligand
substrate time
1
2
3
4
5
6
7
8
9
(R,R)-Me-DuPhos
(R,R)-Me-DuPhosb
(R,R)-Me-DuPhosc
(R,R)-i-Pr-DuPhos
(R,R)-Me-BPE
9a
9a
3 days
1 day
80 59
78 63
48 63
83 -66d
76 37
9a‚HBF4 2 days
Figure 1. Chiral phospholanes with and without P stereocenters.
9a
9a
9a
9a
9a
9a
9b
1 day
3 days
1 day
2 days
2 days
5 days
20 min 86 racf
20 min 95 racf
20 min 93 racf
(R,R)-Me-BPEe
(S,S)-Me-5-Fc
80 40
in high ee using menthol as a chiral auxiliary, but this method
required fractional crystallization of diastereomers, for which
overall yields were not reported.10
Treatment of the known diiodide 711 with a primary
phosphine-borane in the presence of base (NaH or sec-BuLi)
gave the functionalized secondary phosphine-boranes 8a-c
(Scheme 1). Deprotection with DABCO, Et2NH, or more
58 -8d
68 racf
56 racf
(R,S)-CyPF-t-Bu
(R,S)-PPF-t-Bu
10 (R,R)-Me-DuPhos
11 (S,S)-Et-FerroTANEg 9b
12 (S,S)-Me-5-Fc
13 (R,R)-Me-DuPhos
14 nonei
9b
9c
9c
1 h
20 h
48 1:1 drh
49 1.2:1 drh
a
Reactions were carried out at room temperature in toluene with 5 mol
% of the catalyst precursor Pd(diphos*)(trans-stilbene) and 0.12 mmol of
substrate (40 mg of 9a). Isolated yields, after column chromatography, are
Scheme 1. Synthesis of Substrates for Pd-Catalyzed
b
c
reported. Reactions have not been optimized. 300 mg of 9a. With 2
Intramolecular Phosphinationa
equiv of NaOSiMe3; reaction slowed after 40% conversion but went to
d
completion when another equiv of base was added. The preferred
enantiomer of 10a differed for (R,R)-Me-DuPhos/(R,R)-Me-BPE vs (R,R)-
i-Pr-DuPhos/(S,S)-Me-5-Fc. e In THF. f The product was racemic. g Catalyst
precursor ) Pd((S,S)-Et-FerroTANE)(Ph)(I).13 Ca. 5% of the expected
h
byproduct, presumably containing a P-Ph group, was observed. dr )
diastereomeric ratio. i Catalyst precursor ) Pd(OAc)2 (9 mol %); 0.32 mmol
of 9c.
a Men ) (-)-menthyl.
Phenylphosphine 9a slowly gave benzophospholane 10a
in good yields and moderate ee.14 Replacing air-sensitive 9a
with air-stable salt 9a‚HBF4 gave comparable ee’s (entries
1 and 3).15 DuPhos-ligated catalysts (entries 1-4) gave
higher ee’s than those with the ethane-bridged BPE (entries
5 and 6), whereas use of the 1,1′-ferrocene-bridged bis-
(phospholane) Me-5-Fc (entry 7) resulted in very low ee.16
Josiphos-ligated catalysts (entries 8 and 9) gave racemic
conveniently piperazinomethyl polystyrene gave the phos-
phines 9a-c.12
As desired, intramolecular cyclization of secondary phos-
phines 9a-c in the presence of the base NaOSiMe3 and a
(9) (a) Moncarz, J. R.; Laritcheva, N. F.; Glueck, D. S. J. Am. Chem.
Soc. 2002, 124, 13356-13357. (b) Moncarz, J. R.; Brunker, T. J.; Jewett,
J. C.; Orchowski, M.; Glueck, D. S.; Sommer, R. D.; Lam, K.-C.; Incarvito,
C. D.; Concolino, T. E.; Ceccarelli, C.; Zakharov, L. N.; Rheingold, A. L.
Organometallics 2003, 22, 3205-3221. (c) Korff, C.; Helmchen, G. Chem.
Commun. 2004, 530-531. (d) Pican, S.; Gaumont, A.-C. Chem. Commun.
2005, 2393-2395.
(10) Imamoto, T.; Yoshizawa, T.; Hirose, K.; Wada, Y.; Masuda, H.;
Yamaguchi, K.; Seki, H. Heteroat. Chem. 1995, 6, 99-104.
(11) Ripa, L.; Hallberg, A. J. Org. Chem. 1996, 61, 7147-7155.
(12) Sayalero, S.; Pericas, M. A. Synlett 2006, 2585-2588.
(13) Brunker, T. J.; Blank, N. F.; Moncarz, J. R.; Scriban, C.; Anderson,
B. J.; Glueck, D. S.; Zakharov, L. N.; Golen, J. A.; Sommer, R. D.; Incarvito,
C. D.; Rheingold, A. L. Organometallics 2005, 24, 2730-2746.
(14) For synthesis of racemic 10a, see: Quin, L. D.; Rao, N. S. J. Org.
Chem. 1983, 48, 3754-3759. For the P-Et analogue, see: Mann, F. G.;
Millar, I. T. J. Chem. Soc. 1951, 2205-2206.
(15) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295-4298.
(16) Burk, M. J.; Gross, M. F. Tetrahedron Lett. 1994, 35, 9363-9366.
1110
Org. Lett., Vol. 9, No. 6, 2007

product, and several byproducts were formed when the bis-
(phosphetane) (S,S)-Et-FerroTANE was used.
active species in catalysis with 8a might be 9a, formed in
an unfavorable equilibrium by reversible dissociation of
borane from 8a (Scheme 3).18 Consistent with this hypothesis,
Pd((R,R)-Me-DuPhos)-catalyzed cyclization of 8a was
much slower when 1 equiv of BH3(SMe2) was added, and
alkylphosphine boranes 8b,c, in which the borane is expected
to be less labile, did not undergo cyclization.19,20
Benzophospholane-boranes 11a and 11b could also be
prepared from 10 and BH3(SMe2);20 similarly, treatment of
10a with sulfur gave 12 (Scheme 4; the crystal structure in
Figure 2 confirmed the presence of the benzophospholane
ring system).
In contrast, reaction of cyclohexylphosphine 9b was
complete in minutes to give racemic cyclic phosphine 10b
in high yields (entries 10-12). This reaction was ac-
companied by displacement of the chiral diphosphine from
Pd. Similarly, little diastereoselectivity was observed for the
intramolecular coupling of 9c (entries 13 and 14).17
The displacement of the chiral ligand observed in cycliza-
tion of alkylphosphine 9b is a common problem in metal-
catalyzed asymmetric P-C bond formation. It can sometimes
be avoided by using phosphine-boranes instead of phosphines
as substrates.9b,d The alkylphosphine-boranes 8b and 8c did
not undergo Pd-catalyzed cyclization at room temperature,
and byproducts were formed from 8b at 50 °C. However,
the phenylphosphine-borane substrate 8a reacted smoothly
to yield benzophospholane-borane 11a in moderate ee; the
preferred enantiomer was the same as that formed in
cyclization of phosphine 9a (Scheme 3, Table 2).
Scheme 4. Protection of Benzophospholanes
Scheme 3. Pd-Catalyzed Enantioselective Cyclization of
Phosphine-borane 8a and Its Possible Relationship to
Cyclization of Phosphine 9aa
a Catalyst precursor [Pd*] ) Pd(diphos*)(trans-stilbene), diphos*
) (R,R)-Me-DuPhos or (R,R)-Me-BPE. L is a Lewis base, such as
the solvent THF.
Table 2. Pd-Catalyzed Enantioselective Cyclization of
Phosphine-borane 8a and the Analogous Phosphine 9aa
Figure 2. ORTEP diagram of 12.
time
yield
(%)
ee
(%)
entry
ligand
substrate (days)
Both P and C stereochemistries have been controlled by
chiral base-mediated R-deprotonation of the phospholane
ring.21 Instead, stereocontrol of R-alkylation in enantioen-
riched benzophospholanes might occur by a relay from the
P stereocenter. Indeed, R-methylation of 11a gave a 7:1
1
2
3
4
5
6
7
(R,R)-Me-DuPhos
(R,R)-Me-DuPhosb
(R,R)-Me-DuPhos
(R,R)-Me-DuPhos
(R,R)-Me-BPE
8a
8a
9a
9a
8a
9a
9a
6
5
3
1
6
3
1
60
89
80
78
63
76
80
61
70
59
63
36
37
40
(R,R)-Me-BPE
(R,R)-Me-BPE
(18) Imamoto, T.; Oshiki, T.; Onozawa, T.; Matsuo, M.; Hikosaka, T.;
Yanagawa, M. Heteroat. Chem. 1992, 3, 563-575.
(19) Cyclization of 8a (3.0 g) with 5 mol % of Pd(dba)2 and NaOSiMe3
in THF gave racemic 11a in 58% yield; see the Supporting Information for
details.
(20) Ohff, M.; Holz, J.; Quirmbach, M.; Borner, A. Synthesis 1998,
1391-1413.
(21) See refs 2a,b and 3. For related examples, see: (a) Ohashi, A.;
Imamoto, T. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2000, 56,
723-725. (b) Imamoto, T.; Oohara, N.; Takahashi, H. Synthesis 2004,
1353-1358. (c) Tang, W.; Wang, W.; Zhang, X. Angew. Chem., Int. Ed.
2003, 42, 943-946. (d) Tang, W.; Wang, W.; Chi, Y.; Zhang, X. Angew.
Chem., Int. Ed. 2003, 42, 3509-3511. (e) Blake, A. J.; Hume, S. C.; Li,
W.-S.; Simpkins, N. S. Tetrahedron 2002, 58, 4589-4602. (f) Kobayashi,
S.; Shiraishi, N.; Lam, W. W.-L.; Manabe, K. Tetrahedron Lett. 2001, 42,
7303-7306.
a
Reactions were carried out at room temperature in THF with 5 mol %
of the catalyst precursor Pd(diphos*)(trans-stilbene) and 0.14 mmol of
substrate (50 mg of 8a). Isolated yields, after column chromatography, are
reported. Entries 3 and 4 and 6 and 7 are reproduced from Table 1 (entries
b
1 and 2 and 5 and 6) for comparison. 500 mg of 8a.
Because the ee in the cyclization of 8a and its phosphine
analogue 9a was similar with two different catalysts, the true
(17) Blank, N. F.; McBroom, K. C.; Glueck, D. S.; Kassel, W. S.;
Rheingold, A. L. Organometallics 2006, 25, 1742-1748.
Org. Lett., Vol. 9, No. 6, 2007
1111

mixture of diastereomers of 13; the major diastereomer was
isolated in 64% yield (Scheme 5). As expected from steric
Scheme 5. Diastereoselective Methylation of
Benzophospholane 11aa
a Absolute configuration of these compounds has not been
established. The stereochemistry has been drawn arbitrarily to
emphasize the trans relationship of the Me and P-Ph groups in
the major diastereomer of 13.
Figure 3. ORTEP diagram of the major diastereomer of 13.
considerations,21 it contained trans-Ph and -Me groups,
according to X-ray crystallography (Figure 3) and a 1H NMR
NOE study.22
tion in 11a suggest that this chemistry may be useful in the
synthesis of phospholanes for applications in asymmetric
catalysis.
In summary, we have investigated Pd-catalyzed asym-
metric phosphination as a novel approach to the valuable
phospholane ring structure.23 Promising enantioselectivity in
the cyclization of phenylphosphine substrates 8a and 9a
along with the diastereoselective methylation of the R-posi-
Acknowledgment. We thank the National Science Foun-
dation for support, the Department of Education for a
GAANN fellowship to B.J.A., and Robert Crabtree (Yale)
for a valuable suggestion.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(22) For a borane-free benzophospholane isomeric to 13 (Me substitution
in the benzylic position), see: Egan, W.; Tang, R.; Zon, G.; Mislow, K. J.
Am. Chem. Soc. 1971, 93, 6205-6216.
(23) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691-1693.
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