Biphenol-based phosphoramidite ligands for the enantioselective copper-catalyzed conjugate addition of diethylzinc

Article abstract of DOI:10.1021/jo049359m

Phosphoramidite ligands, based on ortho-substituted biphenols and a chiral amine, induce high enantioselectivities (ee's up to 99%) in the copper-catalyzed conjugate addition of dialkylzinc reagents to a variety of Michael acceptors. Particularly, the best reported ee's were obtained for acyclic nitroolefins.

Full text of DOI:10.1021/jo049359m

Bip h en ol-Ba sed P h osp h or a m id ite Liga n d s for th e En a n tioselective
Cop p er -Ca ta lyzed Con ju ga te Ad d ition of Dieth ylzin c
Alexandre Alexakis,* Damien Polet, Ste´phane Rosset, and Se´bastien March
Department of Organic Chemistry, University of Geneva, 30 quai Ernest Ansermet,
Gene`ve 4, Switzerland CH-1211
alexandre.alexakis@chiorg.unige.ch
Received April 16, 2004
Phosphoramidite ligands, based on ortho-substituted biphenols and a chiral amine, induce high
enantioselectivities (ee’s up to 99%) in the copper-catalyzed conjugate addition of dialkylzinc reagents
to a variety of Michael acceptors. Particularly, the best reported ee’s were obtained for acyclic
nitroolefins.
SCHEME 1. Con for m a tion a l Atr op oisom er ism a n d
Der iva tives of L1a
The asymmetric copper-catalyzed conjugate addition
is, nowadays, a well-developed methodology to create
chiral C-C bonds.1 Many efforts have been made in
designing efficient systems and identifying new ligands
to improve enantioselectivities with specific classes of
substrates.2 Among the most efficient ligands, the ones
based on the atropoisomerism of a binaphthol or a
biphenol moiety play a prominent role.3,4 We have
recently demonstrated that phophoramidite ligands based
on the atropoisomerically flexible biphenol unit are also
excellent ligands.5 Thus, the induced atropoisomerism of
ligand L1a , and its analogues L1b and L2a (Scheme 1),
allows high enantioselectivity in the asymmetric conju-
gate addition of dialkylzincs to a variety of Michael
acceptors. Furthermore, improved ee’s were obtained
using diethyl ether as solvent and copper thiophenecar-
boxylate as copper salt.6
The modularity of these phosphoramidite ligands al-
lows for easy variation of the amino part7 as well as the
biphenol part. We describe herein the modification of the
biphenol scaffold of L1a and the consequence in the
enantioselectivity on each substrate under these new
experimental conditions. Using the same amines as in
L1a or L1b, we modified the biphenol core by introducing
different functional groups in ortho and ortho′ positions
(R2, Scheme 2). For some biphenols, it was easier to
introduce an additional substitution on the R1 position,
although not playing an indispensable role. All ligands
L1-L11 were synthesized by reaction of the chiral amine
(a or b) with PCl3 and then addition of the biphenol B2-
B11. They are isolated as white powders or colorless oils
in 12-76% yield.
* To whom correspondence should be addressed. Fax: (41 22) 328
73 96.
(1) (a) Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92, 771. (b)
Alexakis, A. In Transition Metal Catalysed Reactions; Murahashi, S.-
I., Davies, S. G., Eds.; IUPAC Blackwell Science: Oxford, U.K., 1999;
p 303. (c) Tomioka, K.; Nagaoka, Y. In Comprehensive Asymmetric
Catalysis; J acobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer:
New York, 2000; p 1105. (d) Sibi, M. P.; Manyem, S. Tetrahedron 2000,
56, 8033. (e) Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171.
(2) For a recent review, see: Alexakis, A.; Benhaim, C. Eur. J . Org.
Chem. 2002, 3221-3236.
The corresponding biphenols B2-B11 were synthe-
sized by known, or improved, methods. Thus, B3 and B4
8
were obtained by halogenation of biphenol, with SO2Cl2
or Br2,9 respectively. The complete tetrachlorination or
-bromination was easier to carry out than the selective
ortho halogenation. The tetraphenylbiphenol, B5, was
obtained by Suzuki-type coupling of phenyl boronic acid
and MOM-protected B4 (Scheme 3).10 B2, B6, and B7
were synthesized by coupling of the corresponding phe-
nols, with FeSO4 and Na2S2O8 for B211 or catalytic CuBr-
(OH)‚TMEDA for B6 and B7.12 The ortho,ortho′ disily-
(3) (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346-353. (b) Escher,
I. H.; Pfaltz, A. Tetrahedron 2000, 56, 2879-2888. (c) Hu, X.; Chen,
H.; Zhang, X. Angew. Chem., Int. Ed. 1999, 38, 3518-3521. (d) Yan,
M.; Zhou, Z.-Y.; Chan, A. S. C. Chem. Commun. 2000, 115-116. (c)
Borner, C.; Dennis, M. R.; Sinn, E.; Woodward, S. Eur. J . Org. Chem.
2001, 2435-2446. (d) Rimkus, A.; Sewald, N. Synthesis 2004, 135-
146. (e) Hua, Z.; Vassar, V. C.; Choi, H.; Ojima, I. Proc. Natl. Acad.
Sci. 2004, 101, 5411-5416.
(4) Watanabe, T.; Knoepfel, T. F.; Carreira, E. M. Org. Lett. 2003,
5, 4557-4558.
(5) Alexakis, A.; Rosset, S.; Allamand, J .; March, S.; Guillen, F.;
Benhaim, C. Synlett 2001, 9, 1375-1378.
(6) Alexakis, A.; Benhaim, C.; Rosset, S.; Humam, M. J . Am. Chem.
Soc. 2002, 124, 5262-5263.
(8) DeJ ongh, D. C.; Van Fossen, R. Y. J . Org. Chem. 1972, 37, 1129-
1135.
(9) Go´mez-Lor, B.; Echavarren, A. M.; Santos, A. Tetrahedron Lett.
1997, 38, 5347-5350.
(10) Unrau, C. M.; Campbell, M. G.; Snieckus, V. Tetrahedron Lett.
1992, 33, 2773-2776.
(7) We have recently described a new practical synthesis of C2-
symmetrical secondary amines in the following: Alexakis, A.; Gille, S.;
Prian, F.; Rosset, S.; Ditrich, K. Tetrahedron Lett. 2004, 45, 1449-
1451.
10.1021/jo049359m CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/28/2004
5660
J . Org. Chem. 2004, 69, 5660-5667

Biphenol-Based Phosphoramidite Ligands
SCHEME 2. Liga n d s Used in Th is Stu d y
ence of an ortho methoxy group in L6a , designed to see
any additional coordinating effect, shows a similar reactiv-
ity pattern as the two previous ligands L1a and L2a , and
the conjugate adduct has the same absolute configura-
tion. The allyl L9a , and the slightly more hindered meth-
allyl L10a derivatives, showed complementary results
compared to the methyl derivative L1a . Interestingly,
these two ligands were very efficient on the acyclic subs-
trate S2, maintaining excellent efficiency on the cyclic
substrate S1. L11a , with a propyl substituents, gave sim-
ilar results to L10a , although needing one more step to
be synthesized. We therefore chose L9a and L10a to be
tested on a large number of Michael acceptors (Scheme
6). We also tested the ligands with the b series of amine
moiety and the same biphenol part. The results are
shown in Table 2.
All the ligands, and particularly L10b, show a broad
spectrum of applicability, despite the variety of sub-
strates. In most cases, with the exception of chalcone S5,
these new ligands show among the best reported enantio-
selectivities for many substrates. For example S2 afford-
ed 95% ee, the highest reported. S4, the precursor of the
valuable fragrance (R)-muscone also shows a very high
enantioselectivity. Of particular importance are the re-
sults with the five nitroalkenes S8-S12. With the excep-
tion of nitrocyclohexene (although 86% ee is among the
best), the other nitroalkenes provide adducts with 91-96%
ee, an unprecedented result for these Michael acceptors.
In summary, we have disclosed a series of simpler new
phosphorus ligands, based on the induced atropoisom-
erism of the biphenol moiety. In many cases these new
ligands afforded much better results than the parent
ligand based on chiral binaphthol and sometimes the best
reported in the literature. Although no ligand showed
general enantioselectivity on every substrates, these
results serve as a “fine-tuning” study, allowing to improve
the efficiency of 1,4-addition using an optimal ligand for
a definite substrate. Theoretical studies are under way
to get deeper insight on the atropoisomerism of biphenol
systems under the influence of a proximal chiral moiety.
lated biphenol, B8, could be obtained by a sequence
starting with the selective dibromination of biphenol.13
This selectivity was rather low, and the pure dibromi-
nated biphenol could be isolated in only 25% yield. The
next steps were original and involved an O-disilylation
with trimethylchlorosilane, followed by an ortho,ortho′
dimetalation, with t-BuLi, and a retro-Brook rearrange-
ment, in 59% overall yield (Scheme 4). Finally, B9 and
B10 were prepared by a double Claisen rearrangement
of the corresponding bis(allyl) (4) or methallyl (5) ethers.
Instead of heating 4 in Decalin,14 we found a simple
thermic treatment in the Kugelrohr (190 °C) was suf-
ficient to provide B9 in good yield. Under the same
conditions, the Claisen rearrangement of 5 did not take
place. We found, however, that basic conditions were
necessary to obtain B10 in 89% isolated yield (Scheme
5). A simple classical hydrogenation of B9 led, quanti-
tatively, to B11.
To have a general picture of the influence of the ortho
subsituent, ligands L1a -L11a were all tested with
representative enones: a typical cyclic enone, cyclohex-
enone S1, and a typical acyclic one, 5-methyl-3-hexen-
2-one, S2. The results are shown in Table 1.
The first striking results show that too sterically hin-
dered substituents (R1 ) t-Bu or SiMe3, entries 7 and 8)
were unfavorable for catalytic activity. Both conversion
and enantioselectivity fell down using these ligands par-
ticularly with the less reactive acyclic substrate S2. The
presence of electron-withdrawing groups, such as the
chloro and bromo derivatives, L3a and L4a , did not im-
prove enantioselectivity and even shows a deleterious
effect with the acyclic substrate S2. In contrast, the pres-
Exp er im en ta l Section
Ma ter ia ls. Unless otherwise stated, all the reagents were
obtained commercially and were used without further purifica-
tion.
3,3′,5,5′-Tetr a m eth ylbip h en yl-2,2′-d iol (B2).11 To a me-
chanically stirred aqueous solution of FeSO4 heptahydrate
(1.39 g, 5 mmol) in 150 mL of water was suspended 12 mL
(100 mmol) of 2,4-dimethylphenol. A solution of Na2S2O8 (23.9
g, 100 mmol) in 100 mL of water was added dropwise over 4
h. The mixture was then stirred overnight at room tempera-
ture. The resulting suspension was extracted with ethyl
acetate, dried over Na2CO3, and filtered on silica gel. The
solvent was evaporated in vacuo affording 10.3 g of a red-
brown powder, which was purified by a Kugelrohr distillation
(0.4 mmHg, 170 °C) followed by a recrystallization in cyclo-
hexane to obtain 6.66 g (55%) of colorless crystals, mp 139 °C
(lit. mp 137-138 °C).15 1H NMR (400 MHz, CDCl3), δ (ppm):
7.06 (dd, 2H, J ) 1.5, 0.8 Hz), 6.92 (dd, 2H, J ) 2.0, 0.5 Hz),
5.16 (brs, 2H), 2.33 (s, 12H). 13C NMR (100 MHz, CDCl3), δ
(ppm): 149.2, 132.1, 120.1, 128.6, 125.3, 122.3, 20.5, 16.2. IR
(CHCl3): ν 3547, 3295, 2923, 1480, 1323, 1282, 1225, 1216,
1209, 1186, 1118, 1016, 865 cm-1. HRMS (EI) (m/z): calcd for
(11) Qiu, W. U.S. Patent Nï. US 6077979, 2000; p 3.
(12) Collman, J . P.; Zhong, M.; Costanzo, S.; Zhang, C. J . Org. Chem.
2001, 66, 8252-8256.
(13) Ueki, M.; Matsumoto, Y.; J odry, J . J .; Mikami, K. Synlett 2001,
1889-1892. The procedure (personal communication) was described
with the kind permission of Prof. Mikami.
C
16H18O2 (M+•), 242.1307; found, 242.1288.
(14) Moneta, W.; Baret, P.; Pierre, J .-L. Bull. Soc. Chim. Fr. 1988,
6, 995-1004.
(15) Huddle, P. A.; Perold, G. W. J . Chem. Soc., Perkin Trans. 1
1980, 2617-2625.
J . Org. Chem, Vol. 69, No. 17, 2004 5661

Alexakis et al.
SCHEME 3. Syn th esis of Bip h en ol B5
SCHEME 4. Syn th esis of B8 by a Retr o-Br ook Rea r r a n gem en t
SCHEME 5. Syn th esis of B10 by Cla isen Rea r r a n gem en t
SCHEME 6. En on es a n d Nitr oa lk en es Tested in Th is Stu d y
5662 J . Org. Chem., Vol. 69, No. 17, 2004

Biphenol-Based Phosphoramidite Ligands
TABLE 1. Cop p er -Ca ta lyzed Con ju ga te Ad d ition of Dieth ylzin c on to S1 a n d S2
conv,a ee,b absolute confign
entry
ligand
confign of the amine
S1
S2
1
2
3
4
5
6
7
8
L1a c
L2a c
L3a
L4a
L5a
L6a
L7a
L8a
L9a
(S,S)
(S,S)
(S,S)
(S,S)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
>99, 96, Rc
>99, 99, Rc
>99, 84, R
>99, 91, R
>99, 90, S
>99, 91, S
>99, 0
>99, 65, Rc
>99, 58, Rc
16, 31, R
22, 25, R
40, 54, S
>99, 36, S
24, 0
84, 0
9
10
11
>99, 96, S
>99, 89, S
>99, 89, S
>99, 88, S
>99, 95, S
>99, 94, S
L10a
L11a
a
b
Determined by GC-MS. Ee determined by chiral GC. c Taken from ref 6.
TABLE 2. Cop p er -Ca ta lyzed Con ju ga te Ad d ition of Dieth ylzin c on to Va r iou s Mich a el Accep tor s
conv,a ee,b confign
substrate
L9a
L9b
L10a
L10b
S1
S2
S3
S4
S5
S6
S7
S8
>99, 96, S
>99, 88, S
97, 73, S
>99, 60, (+)
90, 11, S
>99, 93, R
>99, 35, (-)
>99, 92, R
>99, 95, R
>99, 96, S
80, 84, S
>99, 81, S
>99, 30, (+)
95, 40, R
>99, 89, S
>99, 95, S
>99, 63, S
>99, 80, (+)
>99, 37, S
71, 89, R
>99, 75, (-)
>99, 90, R
>99, 91, R
>99, 91, R
>99, 87, S
>99, 92, S
>99, 42, S
76, 83, (+)
57, 18, R
30, 80, R
16, 51, R
>99, 30, (-)
>99, 95, R
>99, 95, R
>99, 96, R
>99, 88, (-)
>99, 95, R
>99, 94, R
>99, 94, R
S9
S10
S11
S12
>99, 91, (-)
>99, 86c
a
b
Determined by GC-MS. Ee determined by chiral GC. c Trans major diastereomer obtained with a de of 89%.
3,3′,5,5′-Tetr a ch lor obip h en yl-2,2′-d iol (B3).8 2,2′-Dihy-
droxybiphenyl (B1, 10.0 g, 54 mmol) was dissolved portionwise
in 80 mL of SO2Cl2 (966 mmol) under nitrogen atmosphere.
The solution was then stirred at room temperature. The
reaction was followed by TLC (c-hexane/ethyl acetate, 8:2; Rf
product ) 0.43). After disappearance of the starting material,
water was carefully added to quench the reaction. The mixture
was extracted with ethyl acetate, and the organic layer was
rinsed twice with water, dried over MgSO4, and evaporated
in vacuo. An orange solid was obtained, and recrystallization
of the latter in hexane afforded 9.3 g of B3 as a white powder
(55%), mp 178-179 °C (lit. mp 174-175 °C).8 1H NMR (400
MHz, DMSO-d6), δ (ppm): 9.54 (s, 2H), 7.51 (d, 2H, J ) 2.2
Hz), 7.16 (d, 2H, J ) 2.2 Hz). 13C NMR (100 MHz, DMSO-d6),
δ (ppm): 150.1, 129.9, 129.0, 128.0, 123.2, 122.5. IR (CHCl3):
ν 3533, 3254, 1566, 1461, 1398, 1324, 1286, 1222, 1167, 1074,
mp 300 °C (dec). 1H NMR (500 MHz, DMSO-d6), δ (ppm): 7.65
(d, 2H, J ) 2.0 Hz), 7.33 (d, 2H, J ) 2.0 Hz) 3.39 (brs, 2H). 13
NMR (500 MHz, DMSO-d6), δ (ppm): 155.9, 134.1, 133.0, 130.2,
118.8, 108.5. IR (film): ν 1613, 1541, 1441, 1385, 1255, 1220,
1182, 1154, 1090, 1055 cm-1. MS (electrospray in acetone) did
not give any rational signals.
C
3,3′,5,5′-Tetr a br om o-2,2′-bis(m eth oxym eth yloxy)bip h e-
n yl (1). A solution of B4 (5.0 g, 10 mmol) in 40 mL of dry
THF was slowly added, under nitrogen, to a suspension of NaH
(0.717 g, 30 mmol) in 150 mL of dry THF. After 2 h, a solution
of methoxymethyl chloride (2.3 mL, 2.41 g, 30 mmol) in 20
mL of dry THF was added to the mixture. The resulting
suspension was stirred overnight under nitrogen, and water
was then added to quench the reaction. The organic layer was
washed with an aqueous solution of saturated NaHCO3 and
dried over Na2SO4. After removal of the solvent in vacuo and
recrystallization in ethyl acetate, 1 was obtained as colorless
crystals (4.31 g, 73%), mp 110 °C. 1H NMR (500 MHz, CDCl3),
δ (ppm): 7.75 (d, 2H, J ) 2.2 Hz), 7.48 (d, 2H, J ) 2.2 Hz),
4.87 (s, 4H), 3.07 (s, 6H). 13C NMR (125 MHz, CDCl3), δ (ppm):
151.7, 135.7, 134.3, 133.7, 118.8, 117.1, 99.7, 57.2. IR (film):
ν 2940, 2833, 1541, 1475, 1450, 1434, 1409, 1385, 1277, 1240,
1201, 1150, 1104, 1080, 1053, 920 cm-1. HRMS (EI) (m/z):
calcd for C16H1479Br281Br2O4 (M+•), 589.7625; found, 589.7585.
3,3′,5,5′-Tetr aph en yl-2,2′-bis(m eth oxym eth yloxy)biph e-
n yl (2). Freshly made Pd[P(Ph)3]4 (1.65 g, 1.43 mmol) was
added under argon to a solution of 1 (4.21 g, 7.14 mmol) in
967, 866 cm-1. HRMS (EI) (m/z): calcd for C12H635Cl4O2 (M+•),
35
321.9122; found, 321.9106. HRMS (EI) (m/z): calcd for C12H6
-
Cl337ClO2, 323.9092; found, 323.9091.
3,3′,5,5′-Tetr a br om o-2,2′-d ih yd r oxybip h en yl (B4).9 Bro-
mine (13.8 mL, 268.6 mmol) was rapidly added to a solution
of B1 (10.08 g, 54.1 mmol) in 400 mL of methanol. After 1 h of
stirring, the resulting precipitate was filtered through a
sintered-glass funnel and washed sequentially with aqueous
solutions of NaHCO3, Na2SO3, and water. The resulting white
powder was dissolved in acetone and dried over Na2SO4. Pure
B4 (20.5 g, 76%) was obtained by recrystallization in acetone,
J . Org. Chem, Vol. 69, No. 17, 2004 5663

Alexakis et al.
200 mL of 1,2-dimethoxyethane. This mixture was stirred at
room temperature until all the palladium complex was dis-
solved, and then 50 mL of an aqueous 1 M solution of NaHCO3
was added. After 30 min of stirring, phenylboronic acid (6.97
g, 57.1 mmol) in solution in a minimum of EtOH was added.
This mixture was stirred over 70 h under argon at room
temperature and was then heated to 100 °C over 24 h. The
resulting brown mixture was allowed to cool to RT (room
temperature) and was then filtered through a Celite pad. The
solvent was evaporated in vacuo, and the product was dis-
solved in ethyl acetate. The organic layer was washed respec-
tively with water, aqueous 5% NaOH, 2 N HCl, saturated
NaHCO3, and brine and was then dried over anhydrous
MgSO4. Evaporation of the solvent in vacuo followed by
purification by chromatography (cyclohexane/ethyl acetate, 98:
2) yielded 3.41 g (82%) of pure 2 as a white foam. 1H NMR
(500 MHz, CDCl3), δ (ppm): 7.84 (d, 2H, J ) 2.6 Hz), 7.77-
7.73 (m, 8H), 7.69 (d, 2H, J ) 2.2 Hz), 7.54-7.49 (m, 8H),
7.44-7.39 (m, 4H), 4.62 (s, 4H), 2.81 (s, 6H). 13C NMR (125
MHz, CDCl3), δ (ppm): 152.0, 140.3, 139.9, 137.0, 136.1, 133.9,
130.0, 129.6, 129.2, 128.8, 128.3, 127.2, 127.0, 99.0, 56.3. IR
(film): ν 3032, 2928, 2849, 1600, 1576, 1496, 1471, 1424, 1392,
1313, 1228, 1183, 1153, 1064, 954 cm-1. HRMS (EI) (m/z):
calcd for C40H34O4 (M+•), 578.2457; found, 578.2474.
5.24 (s, 2H, OH), 1.48 (s, 18H), 1.35 (s, 18H). 13C NMR (400
MHz, CDCl3), δ (ppm): 149.8, 143.0, 136.2, 125.3, 124.9, 122.3,
35.2, 34.5, 31.7, 29.7. IR (CHCl3): ν 3531, 2965, 2909, 2871,
1477, 1437, 1364, 1332, 1282, 1236, 1200, 1168, 1096 cm-1
.
HRMS (EI) (m/z): calcd for C28H42O2 (M+•), 410.3185; found,
410.3222.
3,3′-Dibr om obip h en yl-2,2′-d iol (3).18 To a solution of 12.2
mL of sec-butylamine (120 mmol) in 300 mL of dry toluene in
a mechanically stirred 500 mL flask at -30 °C was added
dropwise bromine (3.2 mL, 62 mmol). The resulting orange
suspension was cooled to an internal temperature of -78 °C.
A solution of B1 (5.6 g, 30 mmol) in 10 mL of dry THF was
added dropwise. The resulting mixture was stirred for 6 h at
-78 °C and quenched with 1 M HCl. The layers were
separated, and the aqueous layer was extracted 3 times with
diethyl ether. The combined organic layers were sequentially
washed with an aqueous solution of 10% Na2SO3 and brine,
dried over MgSO4, and evaporated in vacuo. A purification by
silica gel chromatography (pentane/diethyl ether, 7:3) afforded
2.625 g (25%) of 3 as a white powder, mp 127-130 °C (lit. mp
124-125 °C).18 1H NMR (400 MHz, CDCl3), δ (ppm): 7.58 (dd,
2H, J ) 8.1, 1.5 Hz), 7.26 (dd, 2H, J ) 7.6 Hz, 1.5 Hz), 6.96 (t,
2H, J ) 8.1 Hz), 5.94 (s, 2H). 13C NMR (100 MHz, CDCl3), δ
(ppm): 149.5, 132.4, 131.1, 125.6, 122.0, 111.4. IR (CHCl3): ν
3512, 3018, 1439, 1328, 1215 cm-1. HRMS (EI) (m/z): calcd
for C12H879Br81BrO2 (M+•), 343.8871; found, 343.8862.13
3,3′-Bis(t r im et h ylsila n yl)b ip h en yl-2,2′-d iol (B8). 3,3′-
Dibromobiphenyl-2,2′-diol (3) (2.26 g, 6.57 mmol) was dissolved
in 26 mL of dry THF under argon atmosphere. The latter
solution was cooled to -78 °C, and 7.6 mL (14.45 mmol, 2.2
equiv) of a n-BuLi solution (1.9 M in hexane) was added over
5 min followed by trimethylsilyl chloride (1.85 mL, 14.45
mmol). The temperature was slowly raised to 0 °C, and 9.65
mL (14.45 mmol, 2.2 equiv) of a solution of t-BuLi (1.5 M in
hexane) was slowly added over 10 min. The temperature was
then allowed to raise to RT, and the solution was stirred for
about 1 h. An aqueous solution of saturated NH4Cl was added
to the reaction mixture. The resulting layers were separated,
and the aqueous layer was extracted once using methylene
chloride. The combined organic layers were dried over MgSO4
and evaporated in vacuo. Purification on silica gel (c-Hex/
AcOEt, 8:2) afforded 1.33 g (61%) of B8 as a white powder,
mp 93-96 °C (lit. mp 94-95 °C).18 1H NMR (400 MHz, CDCl3),
δ (ppm): 7.49 (dd, 2H, J ) 7.2, 1.5 Hz), 7.29 (dd, 2H, J ) 7.2,
1.7 Hz), 7.08 (t, 2H, J ) 7.3 Hz), 5.32 (s, 2H), 0.37 (s, 18H).
13C NMR (100 MHz, CDCl3), δ (ppm): 158.0, 136.0, 132.1,
126.9, 121.2, 121.1, -0.9. IR (CHCl3): ν 3546, 3262, 2957, 2901,
1589, 1567, 1418, 1322, 1246, 1215, 1179, 1140, 1079, 968
cm-1. HRMS (EI) (m/z): calcd for C18H26O2Si2 (M+•), 330.1471;
found, 330.1476.
3,3′,5,5′-Tetr a p h en yl-2,2′-d ih yd r oxybip h en yl (B5). A
suspension of 2 (2.88 g, 4.98 mmol) in 300 mL of methanol
was heated to 65 °C under nitrogen atmosphere. A 2 mL
volume of fuming hydrochloric acid (37%) was then added.
After 2 h of stirring under these conditions, the mixture was
cooled to RT and an aqueous solution of saturated NaHCO3
was added until no more CO2 was evolved. The methanol was
evaporated in vacuo, and the residue was dissolved in ethyl
acetate, washed with an aqueous solution of saturated
NaHCO3, and dried over MgSO4. Evaporation of the solvent
1
gave B5 as an orange foam (2.41 g, 99%), mp 194-197 °C. H
NMR (500 MHz, CDCl3), δ (ppm): 7.68 (d, 2H, J ) 2.5 Hz),
7.65 (m, 10H), 7.53 (t, 4H, J ) 7.9 Hz), 7.45 (m, 6H), 7.35 (t,
2H, J ) 7.3 Hz), 5.95 (s, 2H). 13C NMR (125 MHz, CDCl3), δ
(ppm): 149.3, 140.2, 137.3, 134.6, 130.0, 129.7, 129.4, 128.9,
128.8, 127.9, 127.0, 126.8, 125.5. IR (film): ν 3512, 3030, 1600,
1497, 1465, 1431, 1308, 1220, 1154, 1074 cm-1. HRMS (EI)
(m/z): calcd for C36H26O2 (M+•), 490.1933; found, 490.1948.
3,3′-Dim eth oxy-5,5′-d im eth ylbip h en yl-2,2′-d iol (B6).16
2-Methoxy-4-methylphenol (0.3 mL, 2.4 mmol) was dissolved
in 4 mL of freshly distilled dichloromethane. A catalytic
amount of CuBrOH‚TMEDA12 (0.007 g, 0.0024 mmol) was
added to this solution. The mixture was then stirred under
pure oxygen atmosphere at room temperature over 4 days. An
aqueous solution of 10% HCl was then added. The two layers
were separated, and the organic layer was dried over MgSO4.
The solvent was removed in vacuo, affording an oil which was
chromatographed on silica gel (cyclohexane/ethyl acetate, 8:2)
affording 0.17 g of B6 as a white powder (52%), mp 133-135
2,2′-Bis(a llyloxy)bip h en yl (4).14 To a well-stirred refluxing
(63 °C) solution of B1 (5 g, 26.9 mmol) and allyl bromide (5.2
mL, 59.18 mmol) in acetone (100 mL) was added potassium
carbonate (12 g, 86.08 mmol) slowly over 15 min. The reaction
was followed by TLC. After 9 h of stirring, 10 g of K2CO3 (72.35
mmol) was added. After a total of 24 h of stirring, the reaction
mixture was allowed to cool to RT and the suspension was
filtered on Celite. The filtrate was concentrated in vacuo, and
the resulting brown oil was dissolved in 100 mL of DCM,
washed with an aqueous solution of 1 M NaOH, rinsed with
water, dried on MgSO4, concentrated in vacuo, and purified
by silica gel chromatography (eluant: DCM) affording 4 (4.8
g) as a viscous oil (99%). 1H NMR (400 MHz, CDCl3), δ (ppm):
7.32 (d, 2H, J ) 7.1), 7.05 (td, 2H, J ) 7.3, 1.0 Hz), 6.98 (d,
2H, J ) 7.8 Hz), 6.0-5.9 (m, 2H), 5.20 (m, 4H), 3.53 (d, 4H, J
1
°C. H NMR (400 MHz, CDCl3), δ (ppm): 6.75 (s, 2H), 6.74 (s,
2H), 5.99 (s, 2H), 3.94 (s, 6H), 2.35 (s, 6H). 13C NMR (100 MHz,
CDCl3), δ (ppm): 147.1, 140.3, 129.6, 124.3, 123.4, 111.3, 56.1,
21.2. IR (CHCl3): ν 3536, 3027, 3019, 2967, 2949, 2861, 2401,
1602, 1492, 1464, 1416, 1361, 1329, 1282, 1256, 1230, 1210,
1190, 1143, 1089, 1053 cm-1. HRMS (EI) (m/z): calcd for
C
16H18O4 (M+•), 274.1205; found, 274.1210.
3,3′,5,5′-Tetr a -ter t-bu tylbip h en yl-2,2′-d iol (B7).17 2,4-Di-
tert-butylphenol (10 g, 48.5 mmol) was dissolved in 75 mL of
freshly distilled dichloromethane. The resulting solution was
cooled to 0 °C, and a catalytic amount of CuBrOH‚TMEDA12
(0.14 g, 0.49 mmol) was added in the solution. The air-opened
mixture was stirred at this temperature over 3 days. An
aqueous solution of 5% H2SO4 was then added at room
temperature to quench the reaction. The two layers were
separated, and the organic layer was dried over MgSO4. The
solvent was removed in vacuo, affording 9.77 g (93%) of B7 as
(16) Ueki, M.; Matsumoto, Y.; J odry, J . J .; Mikami, K. Synlett 2001,
1889-1892.
(17) Heine, H. W.; Ciaccio, J . A.; Carson, K. G.; Taylor, C. M.;
Williams, E. A. J . Org. Chem. 1990, 55, 4039-4043.
(18) Buisman, G. J . H.; Van der Veen, L. A.; Klootwijk, A.; De Lange,
W. G. J .; Kamer, P. C. J .; Van Leeuwen, P. W. N. M.; Vogt, D.
Organometallics 1997, 16, 2929-2939.
1
yellow crystals, mp 200-203 °C. H NMR (400 MHz, CDCl3),
δ (ppm): 7.42 (d, 2H, J ) 2.5 Hz), 7.14 (d, 2H, J ) 2.5 Hz),
5664 J . Org. Chem., Vol. 69, No. 17, 2004

Biphenol-Based Phosphoramidite Ligands
) 6.6 Hz). 13C NMR (100 MHz, CDCl3), δ (ppm): 156.0, 133.6,
131.5, 128.4, 120.4, 116.3, 112.3, 68.9. IR (CHCl3): ν 3072,
3017, 2919, 2866, 1704, 1649, 1594, 1503, 1481, 1443, 1382,
1362, 1284, 1265, 1231, 1162, 1123, 1051, 1022 cm-1. HRMS
(EI) (m/z): calcd for C18H18O2 (M+•), 266.1307; found, 266.1294.
cm-1. HRMS (EI) (m/z): calcd for C18H22O2 (M+•), 270.1620;
found, 270.1619.
(S,S)-(5,7-Diox-6-p h osp h a d ib en zo[a ,c]cycloh ep t en -6-
yl)bis(1-p h en yleth yl)a m in e (L1a ). Ligand L1a was pre-
pared according to the literature.5
3,3′-Dia llylb ip h en yl-2,2′-d iol (B9).14 2,2′-Bis(allyloxy)-
biphenyl (4) (1 g, 3.8 mmol) was heated (Kugelrohr 190 °C,
ambient pressure) over 24 h under nitrogen atmosphere. The
resulting brown oil was distilled in the same apparatus (200
°C 0.4 mmHg), and B9 was obtained pure as a colorless oil
(S,S)-Bis(1-ph en yleth yl)(2,4,8,10-tetr am eth yl-5,7-dioxa-
6-p h osp h a d ib en zo[a ,c]cycloh ep t en -6-yl)a m in e (L2a ).
Ligand L1a was prepared according to the literature.5
(S,S)-Bis(1-p h en yleth yl)(2,4,8,10-tetr a ch lor o-5,7-d ioxa -
6-phosphadibenzo[a ,c]cyclohepten-6-yl)amine (L3a).Ligand
L3a was prepared according to the general procedure (see
Supporting Information) using bis[(S)-phenylethyl]amine (0.135
g, 0.60 mmol) and B3 (0.192 g, 0.60 mmol). Purification by
flash chromatography on neutral alumina using toluene as
eluent gave L3a as a white foam in 45% yield (0.156 g). [R]D
1
(0.80 g, 80% yield). H NMR (400 MHz, CDCl3), δ (ppm): 7.11
(dd, 2H J ) 7.4, 1.5 Hz), 7.05 (dd, 2H, J ) 7.6, 1.5 Hz), 6.90 (t,
2H, J ) 7.3 Hz), 5.96 (ddt, 2H, J ) 16.9, 10.1, 6.6 Hz), 5.36 (s,
2H), 5.05 (m, 4H), 3.39 (d, 4H, J ) 6.6 Hz). 13C NMR (100
MHz, CDCl3), δ (ppm): 151.2, 136.5, 130.6, 129.3, 127.3, 123.4,
121.3, 116.3, 35.0. IR (CHCl3): ν 3545, 3082, 3013, 2914, 1360,
1639, 1587, 1447, 1326, 1231, 1215, 1195, 1167, 1115, 1074
cm-1. HRMS (EI) (m/z): calcd for C18H18O2 (M+•), 266.1307;
found, 266.1299.
1
) -493.0 (c ) 0.8 in toluene). H NMR (400 MHz, CDCl3), δ
(ppm): 7.53 (d, 1H, J ) 2.5 Hz), 7.48 (d, 1H, J ) 2.5 Hz), 7.33
(d, 1H, J ) 2.5 Hz), 7.29 (d, 1H, J ) 2.5 Hz), 7.10-7.40 (m,
10H), 4.66 (m, 2H), 1.77 (d, 6H, J ) 7.1 Hz). 13C NMR (100
MHz, CDCl3), δ (ppm): 147.0 (d), 145.8, 142.4, 132.3 (d), 130.9,
130.8, 130.3, 130.0, 129.8, 128.9, 128.7, 128.5, 128.2, 128.1,
127.9 (d), 126.9, 53.1, 53.0, 21.9. 31P NMR (162 MHz, CDCl3),
δ (ppm): 148.6.
2,2′-Bis((2-m et h yla llyl)oxy)b ip h en yl (5). To a well-
stirred refluxing (63 °C) suspension of B1 (2.79 g, 15 mmol),
methallyl chloride (6.25 mL, 63.5 mmol), and NaI (0.2 g, 1.32
mmol) in acetone (30 mL) was added potassium carbonate (6.7
g, 48 mmol) slowly over 30 min. The reaction was followed by
TLC (DCM, Rf product ) 0.90, Rf of starting material ) 0.28).
After 99 h of stirring, the reaction mixture was allowed to cool
to RT and the suspension was filtered on Celite. The filtrate
was concentrated in vacuo, and the resulting brown oil was
dissolved in 100 mL of DCM, washed with an aqueous solution
of 1 M NaOH, rinsed with water, dried on MgSO4, concentrated
in vacuo, and purified by silica gel chromatography (eluant:
(S,S)-Bis(1-p h en yleth yl)(2,4,8,10-tetr a br om o-5,7-d ioxa -
6-phosphadibenzo[a ,c]cyclohepten-6-yl)amine (L4a).Ligand
L4a was prepared according to the general procedure usingbis-
[(S)-phenylethyl]amine (0.104 g, 0.462 mmol) and B4 (0.232
g, 0.462 mmol). Purification by flash chromatography on neu-
tral alumina using toluene as eluent gave L4a as a white solid
1
in 55% yield (0.192 g). [R]D ) -241.0 (c ) 2.6 in toluene). H
NMR (400 MHz, CDCl3), δ (ppm): 7.84 (d, 1H, J ) 2.5 Hz),
7.79 (d, 1H, J ) 2.5 Hz), 7.51 (d, 1H, J ) 2.2 Hz), 7.46 (d, 1H,
J ) 2.0 Hz), 7.18-7.13 (m, 10H), 4.66 (m, 2H), 1.80 (d, 6H, J
) 6.8 Hz). 13C NMR (100 MHz, CDCl3), δ (ppm): 148.5, 147.4,
135.9, 135.6, 132.6 (d), 131.8, 131.0, 127.9, 126.9, 118.6, 117.6,
117.4, 116.2, 53.1, 53.0, 27.0. 31P NMR (162 MHz, CDCl3), δ
(ppm): 147.8.
1
DCM) affording 5 (3.55 g, 80%) as a viscous oil. H NMR (400
MHz, CDCl3), δ (ppm): 7.37-7.34 (m, 4H), 7.07 (t, 2H, J ) 6.3
Hz), 6.98 (d, 2H, J ) 1.0 Hz), 4.96 (s, 2H), 4.89 (s, 2H), 4.42 (s,
4H), 1.73 (s, 6H). 13C NMR (100 MHz, CDCl3), δ (ppm): 156.2,
141.1, 131.6, 128.4, 120.4, 112.2, 111.6, 71.8, 19.3. IR
(CHCl3): ν 3078, 3020, 3978, 2916, 2856, 1659, 1594, 1583,
1504, 1481, 1443, 1377, 1301, 1265, 1231, 1162, 1125, 1061,
1020 cm-1. HRMS (EI) (m/z): calcd for C20H22O2 (M+•),
294.1620; found, 294.1623.
1,1′-(4,4′,6,6′-Tet r a p h en yl)b ip h en ylp osp h in it e-(R,R)-
bis(p h en yleth yl)a m id ite (L5a ). Ligand L5a was prepared
according to the general procedure using bis[(R)-phenylethyl]-
amine (0.14 g, 0.62 mmol) and B5 (0.232 g, 0.462 mmol).
Purification by flash chromatography on neutral alumina
using toluene as eluent gave L5a as a white foam in 71% yield
(0.323 g). [R]D ) +327° (c ) 0.23 in toluene). 1H NMR (400
MHz, CDCl3), δ (ppm): 7.80 (m, 4H), 7.69 (m, 4H), 7.48 (m,
7H), 7.38 (m, 4H), 7.29 (m, 5H), 7.18 (m, 2H), 7.02 (t, 2H, J )
7.3 Hz), 6.93 (t, 3H, J ) 7.3 Hz), 6.74 (d, 3H, J ) 7.0 Hz), 4.42
(s, 2H), 1.11 (d, 6H, J ) 7.1 Hz). 13C NMR (100 MHz, CDCl3),
δ (ppm): 147.7, 140.3, 140.3, 138.3, 137.8, 137.6, 136.8, 135.8,
134.2, 132.7, 131.8, 130.3, 129.7, 129.5, 129.3, 129.0, 128.8-
(d), 128.5, 128.2, 128.1, 128.0, 127.6, 127.4, 127.3, 127.1, 127.0,
126.1, 125.2, 52.0, 29.7, 21.4. 31P NMR (162 MHz, CDCl3), δ
(ppm): 145.9.
3,3′-Bis(2-m eth yla llyl)bip h en yl-2,2′-d iol (B10). 2,2′-Bis-
((2-methylallyl)oxy)biphenyl (5) (2.65 g, 8.99 mmol) was mixed
with lithium methoxide (0.725 g, 18 mmol) and heated in a
Kugelrohr (190 °C, 1 atm) during 14 h under nitrogen
atmosphere. The resulting salt is then hydrolyzed with aque-
ous 1 M HCl, extracted twice with diethyl ether, rinsed with
water, and dried over sodium sulfate. The solvent is removed
in vacuo to afford 2.35 g (89%) of B10 as a brown oil. 1H NMR
(400 MHz, CDCl3), δ (ppm): 7.24 (dd, 2H, J ) 7.8, 1.5 Hz),
7.21 (dd, 2H, J ) 7.7, 1.5 Hz), 7.05 (t, 2H, J ) 7.4 Hz), 5.77 (s,
2H), 4.95 (s, 2H), 4.87 (s, 2H), 3.51 (s, 4H), 1.84 (s, 6H). 13C
NMR (100 MHz, CDCl3), δ (ppm): 154.6, 144.8, 131.0, 129.7,
126.7, 124.7, 121.2, 112.2, 39.2, 22.4. IR (CHCl3): ν 3545, 3438,
3078, 3012, 2975, 2917, 1649, 1587, 1445, 1376, 1326, 1230,
1202, 1168, 1106, 1076 cm-1. HRMS (EI) (m/z): calcd for
(R,R)-(4,8-Dim eth oxy-2,10-d im eth yl-5,7-d ioxa -6-p h os-
p h a d ib e n zo[a ,c]cycloh e p t e n -6-yl)b is(1-p h e n yle t h yl)-
a m in e (L6a ). Ligand L6a was prepared according to the
general procedure using bis[(R)-phenylethyl]amine (0.14 g,
0.62 mmol) and B6 (0.17 g, 0.62 mmol). Purification by flash
chromatography on neutral alumina using pure toluene as
C
20H22O2 (M+•), 294.1620; found, 294.1612.
3,3′-Dip r op ylbip h en yl-2,2′-d iol (B11). B9 (1.548 g, 5.81
mmol) was dissolved in 20 mL of methanol, followed by an
addition of palladium on charcoal (10%, 75 mg, 0.07 mmol).
The system was purged five times with nitrogen and then five
times with hydrogen. The reaction mixture was stirred over 2
h under 1 atm of hydrogen and then filtered on Celite. Solvent
was evaporated in vacuo. Purification by flash chromatography
on silica gel (c-hexane/ethyl acetate, 8:2) afforded 1.193 g (81%)
of B11 as a pale yellow oil. 1H NMR (400 MHz, CDCl3), δ
(ppm): 7.22 (dd, 2H, J ) 7.3, 1.5 Hz), 7.10 (dd, 2H, J ) 7.6,
1.8 Hz), 6.98 (t, 2H, J ) 7.6 Hz), 5.18 (s, 2H), 2.69 (t, 4H, J )
7.6 Hz), 1.70 (sext, 4H, J ) 7.3 Hz), 1.02 (t, 6H, J ) 7.3 Hz).
13C NMR (100 MHz, CDCl3), δ (ppm): 151.3, 130.8, 130.1,
128.4, 122.3, 120.9, 32.4, 23.0, 14.2. IR (CHCl3): ν 3545, 3295,
2963, 2934, 2873, 2361, 1587, 1448, 1326, 1218, 1168, 1118
eluent gave L6a as a white foam in 31% yield (0.10 g). [R]D
)
+201.3 (c ) 1.17 in CHCl3). 1H NMR (400 MHz, CDCl3), δ
(ppm): 7.22-7.24 (m, 4H), 7.13-7.05 (m, 6H), 6.87 (d, 2H, J
) 7.3 Hz), 6.75 (d, 2H, J ) 5.8 Hz), 4.62 (m, 2H), 3.93 (s, 3H),
3.75 (s, 3H), 2.38 (s, 6H), 1.75 (d, 6H, J ) 7.1 Hz). 13C NMR
(100 MHz, CDCl3), δ (ppm): 151.8, 151.3, 143.4, 139.1, 139.0,
138.3, 133.8, 133.0, 131.9, 130.6, 128.9, 128.0, 127.5, 126.3,
121.9, 121.8, 113.1, 112.3, 56.4, 55.7, 53.0, 52.9, 21.9, 22.0, 21.5,
21.4. 31P NMR (162 MHz, CDCl3), δ (ppm): 145.9.
(R,R)-Bis(1-p h en ylet h yl)(2,4,8,10-t et r a -ter t-b u t yl-5,7-
dioxa-6-ph osph adiben zo[a ,c]cycloh epten -6-yl)am in e (L7a).
Ligand L7a was prepared according to the general procedure
using bis[(R)-phenylethyl]amine (0.25 g, 1.11 mmol) and B7
J . Org. Chem, Vol. 69, No. 17, 2004 5665

Alexakis et al.
(0.456 g, 1.11 mmol). Purification by flash chromatography on
neutral alumina using toluene as eluent gave L7a as a white
foam in 30% yield (0.22 g). [R]D ) +171.8 (c ) 1.08 in CHCl3).
1H NMR (400 MHz, CDCl3), δ (ppm): 7.50 (d, 1H, J ) 2.3 Hz),
7.42 (d, 1H, J ) 2.3 Hz), 7.21 (d, 1H, J ) 2.5 Hz), 7.20-7.00
(m, 11H), 4.70-4.35 (brs, 2H), 1.65 (s, 9H), 1.38 (s, 18H), 1.14
(s, 9H). 13C NMR (100 MHz, CDCl3), δ (ppm): 168.2, 165.6,
147.9, 147.8(d), 145.8, 145.2, 140.2, 139.6, 132.9, 132.6 (d),
127.9, 126.9, 126.1, 124.1, 124.0, 35.6, 35.1, 34.6 (d), 31.8, 31.7,
31.6 (d), 30.8, 30.7, 19.9. 31P NMR (162 MHz, CDCl3), δ (ppm):
149.1.
(R,R)-(4,8-Bis(tr im eth ylsila n yl)-5,7-d ioxa -6-p h osp h a d -
ibenzo[a ,c]cyclohepten-6-yl)bis(1-phenylethyl)amine (L8a).
Ligand L8a was prepared according to the general procedure
using bis[(R)-phenylethyl]amine (0.225 g, 1.0 mmol) and B8
(0.331 g, 1.0 mmol). Purification by flash chromatography on
neutral alumina using toluene as eluent gave L8a as a white
foam in 12% yield (0.07 g). [R]20D ) +353.1 (c ) 1.02 in CHCl3).
1H NMR (400 MHz, CDCl3), δ (ppm): 7.54 (dd, 1H, J ) 7.3,
1.5 Hz), 7.50 (dd, 1H, J ) 7.3, 1.8 Hz), 7.41 (dd, 1H, J ) 7.6,
1.5 Hz), 7.31 (dd, 1H, J ) 7.8, 1.8 Hz), 7.25-7.19 (m, 4H), 7.11
(m, 8H), 4.54 (brs, 2H), 1.72-1.58 (m, 6H), 0.49 (s, 9H); 0.15
(s, 9H). 13C NMR (100 MHz, CDCl3), δ (ppm): 156.0 (d), 155.7,
155.6, 135.5, 135.1, 133.0, 131.7, 131.6, 131.0, 130.7(d), 128.4,
127.9, 127.8, 126.7, 124.0, 123.8, 53.2, 53.1, 1.1, 0.0, -0.1. 31P
NMR (162 MHz, CDCl3), δ (ppm): 149.4.
(R,R)-(4,8-Dia llyl-5,7-d ioxa -6-p h osp h a d iben zo[a ,c]cy-
cloh epten -6-yl)bis(1-ph en yleth yl)am in e (L9a). Ligand L9a
was prepared according to the general procedure using bis-
[(R)-phenylethyl]amine (0.266 g, 1.18 mmol) and B9 (0.315 g,
1.18 mmol). Purification by flash chromatography on neutral
alumina using toluene as eluent, gave L9a as a white foam in
64% yield (0.39 g). [R]D ) +248.8 (c ) 0.98 in toluene). 1H NMR
(300 MHz, CDCl3), δ (ppm): 7.40-7.00 (m, 16H), 6.10 (ddt, 1H,
J ) 17.0, 10.0, 6.8 Hz), 5.89 (ddt, 1H, J ) 17.1, 10.0, 6.6 Hz),
5.23 (dq, 1H, J ) 17.1, 1.7 Hz), 5.17 (dq, 1H, J ) 12.5, 1.7
Hz), 5.03 (dq, 1H, J ) 13.4, 1.7 Hz), 4.93 (dq, 1H, J ) 15.3,
1.7 Hz), 4.71 (m, 2H), 3.92 (dd, 1H, J ) 15.1, 6.6 Hz), 3.59
(dd, 1H, J ) 16.8, 6.9 Hz), 3.23 (d, 2H, J ) 6.6 Hz), 1.76 (d,
6H, J ) 6.4 Hz). 13C NMR (75 MHz, CDCl3), δ (ppm): 137.1,
137.0, 133.2, 132.3, 130.0, 129.9, 128.9, 128.8, 128.7, 128.4,
128.2, 127.2, 124.8, 124.2, 116.6, 116.1, 53.0, 52.9, 35.9, 34.9.
31P NMR (122 MHz, CDCl3), δ (ppm): 145.5.
(R,R)-(4,8-Dia llyl-5,7-d ioxa -6-p h osp h a d iben zo[a ,c]cy-
cloh ep ten -6-yl)bis(1-p h en ylp r op yl)a m in e (L9b). Ligand
L9b was prepared according to the general procedure using
bis[(R)-1-phenylpropyl)]amine (0.253 g, 1.0 mmol) and B9
(0.266 g, 1.0 mmol). Purification by flash chromatography on
neutral alumina using toluene as eluent gave L9b as a
colorless oil in 19% yield (0.11 g). [R]D ) +219.1 (c ) 1.08 in
CHCl3). 1H NMR (500 MHz, CDCl3), δ (ppm): 7.36-6.95 (m,
16H), 6.07 (ddt, 1H, J ) 16.9, 10.1, 6.8 Hz), 5.84(ddt, 1H, J )
13.6, 10.4, 6.5 Hz), 5.20 (dq, 1H, J ) 17.0, 1.7 Hz), 5.16 (dq,
1H, J ) 10.0, 1.8 Hz), 4.99 (dq, 1H, J ) 10.0, 1.8 Hz), 4.85
(dq, 1H, J ) 17.0, 1.9 Hz), 4.30 (m, 2H), 3.88 (dd, 1H, J )
15.2, 6.7 Hz), 3.59 (dd, 1H, J ) 15.3, 6.8 Hz), 3.11 (dd, 1H, AB
system, J ) 14.7, 6.3 Hz), 3.07 (dd, 1H, AB system J ) 14.6,
7.0 Hz), 2.34 (m, 2H), 2.10 (m, 2H), 0.81 (t, 6H, J ) 7.4 Hz).
13C NMR (125 MHz, CDCl3), δ (ppm): 149.4 (d), 148.8 (d), 136.7
(d), 132.8, 131.8, 131.7, 131.6, 130.8 (d), 129.6, 129.5, 129.0,
128.6, 128.5 (d), 128.2, 127.7, 127.6, 126.6, 125.3, 124.2, 123.8,
116.1, 115.6, 60.1, 35.3, 34.4, 29.7, 12.0, 11.8. 31P NMR (203
MHz, CDCl3), δ (ppm): 143.3.
4.05 (d, 1H, J ) 14.5 Hz), 3.50 (d, 1H, J ) 14.5 Hz), 3.30 (d,
1H, AB system, J ) 15.6 Hz), 3.23 (d, 1H, AB system, J )
15.6 Hz), 1.91-1.73 (m, 12H). 13C NMR (75 MHz, CDCl3), δ
(ppm): 150.0, 149.9, 149.2(d), 144.8, 144.5, 132.3, 132.2, 132.1,
132.0, 131.5, 130.8(d), 130.3, 130.2, 128.7, 128.6, 128.2, 127.9,
126.8, 124.3, 123.7, 112.0, 111.7, 52.5, 52.4, 39.5, 38.1, 22.9,
22.8, 22.6. 31P NMR (122 MHz, CDCl3), δ (ppm): 145.0.
(R,R)-[4,8-Bis(2-m eth ylallyl)-5,7-dioxa-6-ph osph adiben -
zo[a ,c]cycloh ep ten -6-yl]bis(1-p h en yleth yl)a m in e (L10b).
Ligand L10b was prepared according to the general procedure
using bis[(R)-1-phenyl-propyl)]amine (0.253 g, 1.0 mmol) and
B10 (0.294 g, 1.0 mmol). Purification by flash chromatography
on neutral alumina using toluene as eluent gave L10b as a
colorless oil in 32% yield (0.326 g). [R]D ) +215.4 (c ) 0.81 in
CHCl3). 1H NMR (300 MHz, CDCl3), δ (ppm): 7.26-6.99 (m,
16H), 4.75 (d, 1H, J ) 0.4 Hz), 4.66 (d, 1H, J ) 0.6 Hz), 4.65
(d, 1H, J ) 0.4 Hz), 4.31 (s, 1H), 4.19 (brs, 2H), 3.84 (d, 1H, J
) 8.7 Hz), 3.32 (d, 1H, J ) 8.7 Hz), 3.01 (d, 1H, AB system, J
) 9.3 Hz), 2.95 (d, 1H, AB system, J ) 9.4 Hz), 2.25-1.80 (m,
4H), 1.67 (s, 3H), 1.48 (s, 3H), 0.90-0.25 (m, 6H). 13C NMR
(75 MHz, CDCl3), δ (ppm): 149.8, 149.7, 149.1 (d), 144.9, 144.6,
132.2 (d), 131.9 (d), 131.3, 130.8 (d), 130.1, 128.6, 128.5, 127.7,
126.6, 124.1, 123.5, 111.8, 111.6, 50.7, 39.2, 37.8, 29.7, 22.7,
22.4, 11.8. 31P NMR (122 MHz, CDCl3), δ (ppm): 142.6.
(S,S)-(4,8-Dip r op yl-5,7-d ioxa -6-p h osp h a d ib en zo[a ,c]-
cycloh ep ten -6-yl)bis(1-p h en yleth yl)a m in e (L11a ). Ligand
L11a was prepared according to the general procedure using
bis[(S)-phenylethyl]amine (0.834 g, 3.7 mmol) and B11 (1.00
g, 3.7 mmol). Purification by flash chromatography on neutral
alumina using toluene as eluent gave L11a as a colorless oil
in 53% yield (1.034 g). [R]D ) -241.64 (c ) 1.05 in toluene).
1H NMR (400 MHz, CDCl3), δ (ppm): 7.36-7.11 (m, 16H), 4.70
(brs, 2H), 3.26-3.19 (m, 1H), 2.74-2.67 (m, 1H), 2.53 (t, 2H,
J ) 7.8 Hz), 1.83-1.57 (m, 10H), 1.08 (t, 2H, J ) 7.3 Hz), 0.93
(t, 2H, J ) 7.3 Hz). 13C NMR (100 MHz, CDCl3), δ (ppm): 150.0,
149.9, 149.2 (d), 144.8, 144.5, 132.3, 132.2, 132.1, 132.0, 131.5,
130.8 (d), 130.3, 130.2, 128.7, 128.6, 128.2, 127.9, 126.8, 124.3,
123.7, 112.0, 111.7, 52.5, 52.4, 39.5, 38.1, 22.9, 22.8, 22.6. 31P
NMR (162 MHz, CDCl3), δ (ppm): 145.0.
3-Eth ylcycloh exa n on e. Enantiomer separation by chiral
GC: Lipodex E (25 m, H2, 50 cm‚s-1). T: 60 °C. Rt ) 24.7 min
for enantiomer (R), and Rt ) 28.1 min for enantiomer (S).
3-Eth ylcycloh ep ta n on e. Enantiomer separation by chiral
GC: Lipodex E (25 m, H2, 50 cm‚s-1). T: 60 °C. Rt ) 45.6 min
for enantiomer (S), and Rt ) 47.2 min for enantiomer (R).
3-Eth ylcyclop en ta d eca n on e. Enantiomer separation by
chiral GC: Hydrodex â-3P, (25 m, H2, 50 cm‚s-1). T: 140 °C,
60 min; 1°/min. Rt ) 56.9 min for enantiomer (-)-(R), and Rt
) 58.2 min for enantiomer (+)-(S).
4-Eth yln on a n -2-on e. Enantiomer separation by chiral GC:
Lipodex E (25 m, H2, 50 cm‚s-1). T: 60 °C; 1°/min. Rt ) 17.8
min for enantiomer (S), and Rt ) 18.3 min for enantiomer (R).
4-P h en ylh exa n -2-on e. Enantiomer separation by chiral
GC: Lipodex E (25 m, H2, 50 cm‚s-1). T: 75 °C. Rt ) 39.9 min
for enantiomer (S), and Rt ) 41.8 min for enantiomer (R).
1,3-Dip h en ylp en ta n -2-on e. Enantiomer separation by
chiral SFC: Chiralcel OD-H, 0.25 m, 2% MeOH for 6 min, 3%
until 15 min, 2 mL‚min-1. Rt ) 5.6 min for enantiomer (+)-
(S), and Rt ) 6.3 min for enantiomer (-)-(R).
4-Eth yl-5-m eth ylh exa n on e. Enantiomer separation by
chiral GC: Lipodex E (25 m, H2, 50 cm‚s-1). T: 60 °C; 1°/min.
Rt ) 7.8 min for enantiomer (R), and Rt ) 8.3 min for
enantiomer (S).
(1-(Nitr om eth yl)p r op yl)ben zen e. Enantiomer separa-
tion: Lipodex E (25 m, H2, 50 cm‚s-1). T: 100 °C; 1 °C/min. Rt
) 17.0 min for enantiomer (S), and Rt ) 17.6 min for
enantiomer (R).
(R,R)-[4,8-Bis(2-m eth ylallyl)-5,7-dioxa-6-ph osph adiben -
zo[a ,c]cycloh ep ten -6-yl]bis(1-p h en yleth yl)a m in e (L10a ).
Ligand L10a was prepared according to the general procedure
using bis[(R)-phenylethyl]amine (0.225 g, 1.0 mmol) and B10
(0.294 g, 1.0 mmol). Purification by flash chromatography on
neutral alumina using toluene as eluent gave L10a as a
colorless oil in 53% yield (0.290 g). [R]D ) +249.1 (c ) 1.06 in
CHCl3). 1H NMR (300 MHz, CDCl3), δ (ppm): 7.46-7.21 (m,
16H), 4.95 (s, 1H), 4.87 (s, 2H), 4.76 (brs, 2H), 4.55 (s, 1H),
1-Met h yl-4-(1-(n it r om et h yl)p r op yl)b en zen e. Enanti-
omer separation by chiral GC: Lipodex E (25 m, H2, 50 cm‚s-1).
T: 100 °C; 1°/min. Rt ) 19.2 min for enantiomer (S), and Rt )
19.5 min for enantiomer (R).
5666 J . Org. Chem., Vol. 69, No. 17, 2004

Biphenol-Based Phosphoramidite Ligands
1-Meth oxy-4-(1-(n itr om eth yl)p r op yl)ben zen e. Enanti-
omer separation by chiral SFC: Chiralcel OD-H, 250 mm, 2%
MeOH 6 min, 3% until 15 min, 2 mL‚min-1. Rt ) 3.6 min for
enantiomer (R), and Rt ) 3.9 min for enantiomer (S).
2-(1-(Nitr om eth yl)p r op yl)fu r a n . Enantiomer separation
by chiral GC: Hydrodex â-3P (25 m, H2, 50 cm‚s-1). T: 100
°C. Rt ) 11.2 min for enantiomer (-), and Rt ) 11.6 min for
enantiomer (+).
1-Eth yl-2-n itr ocycloh exa n e. Enantiomer separation by
chiral GC: Lipodex E (25 m, H2, 50 cm‚s-1). T: 60 °C; 3°/min.
Rt ) 16.16 (trans), 16.37 (cis), 16.78 (cis), and 17.12 min
(trans).
Ack n ow led gm en t. D.P. wishes to thank Dr. J .-C.
Kizirian for fruitful discussions. The authors thank the
BASF Co. for the generous gift of chiral amines and the
Swiss National Research Foundation Grant No. 20-
068095.02 and COST action D24/0003/01 (OFES con-
tract No. C02.0027) for financial support.
Su p p or tin g In for m a tion Ava ila ble: Spectral data for all
compounds and general procedures. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O049359M
J . Org. Chem, Vol. 69, No. 17, 2004 5667