Phosphinite thioethers derived from chiral epoxides. Modular P, S -ligands for pd-catalyzed asymmetric allylic substitutions

Article abstract of DOI:10.1021/jo100223w

A new family of modular P,S-ligands has been prepared from enantiopure arylglycidols. These ligands have been iteratively optimized with respect to four different structural parameters for use in Pd-catalyzed allylic substitutions. As a final output, highly active and enantioselective ligands for these synthetically important transformations have been developed, and the factors controlling their catalytic behavior have been rationalized. From a methodological point of view, a convenient procedure for the regioselective ring-opening of cis-glycidic esters with bulky thiols to yield the corresponding β-alkylthio-α-hydroxy carboxylic acids has been developed.

Full text of DOI:10.1021/jo100223w

pubs.acs.org/joc
Phosphinite Thioethers Derived from Chiral Epoxides. Modular
P,S-Ligands for Pd-Catalyzed Asymmetric Allylic Substitutions
,†,‡
Xisco Caldentey†,‡ and Miquel A. Pericas*
ꢀ
†Institute of Chemical Research of Catalonia (ICIQ), Av. Paısos Catalans 16, E-43007 Tarragona, Spain, and
¨
Departament de Quımica Organica, Universitat de Barcelona, E08028 Barcelona, Spain
‡
´
ꢀ
mapericas@iciq.es
Received February 11, 2010
A new family of modular P,S-ligands has been prepared from enantiopure arylglycidols. These
ligands have been iteratively optimized with respect to four different structural parameters for use in
Pd-catalyzed allylic substitutions. As a final output, highly active and enantioselective ligands for
these synthetically important transformations have been developed, and the factors controlling their
catalytic behavior have been rationalized. From a methodological point of view, a convenient
procedure for the regioselective ring-opening of cis-glycidic esters with bulky thiols to yield the
corresponding β-alkylthio-R-hydroxy carboxylic acids has been developed.
Introduction
While the use of bidentate ligands with P,N coordination
mode has become a mature tool in asymmetric catalysis,4 the
use of related P,S-ligands has gained considerable momen-
tum in recent times.5 These ligands present a key structural
property that makes them very attractive in asymmetric
Metal-catalyzed asymmetric reactions have become one of
the most powerful tools for the production of enantiomeri-
cally enriched compounds. Although the use of numerous
chiral ligands has been reported, the design and synthesis of
new types of ligands with improved performance continues
to attract the interest of synthetic chemists.1
In general, the design of new catalysts makes use of either
C2-symmetrical ligands, resulting in catalytic systems with
restricted numbers of competing diastereomeric transition
states,2 or involves ligands containing different donor atoms,
able to generate electronic asymmetry on the metal. This
asymmetry can be transmitted to reacting molecules bonded
to the metal (for instance, through the trans effect)3 and has
the potential to control both the stability and reactivity of
metal-substrate intermediates.
(5) For some recent publications of chiral P,S-ligands for asymmetric
catalysis, see: (a) Herrman, J.; Pregosin, P. S.; Salzmann, R. Organometallics
1995, 14, 3311. (b) Hiroi, K.; Suzuki, Y. Tetrahedron Lett. 1998, 39, 6499.
(c) Enders, D.; Peters, R.; Runsink, J.; Bats, J. W. Org. Lett. 1999, 11, 1863.
(d) Hauptman, E.; Fagan, P. J.; Marshall, W. Organometallics 1999, 18, 2061.
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(e) Pamies, O.; Dieguez, M.; Net, G.; Ruiz, A.; Claver, C. Organometallics
2000, 19, 1488. (f) Evans, D. A.; Campos, K. R.; Tedrow, J. S.; Michael, F. E.;
Michel, R. G. J. Am. Chem. Soc. 2000, 122, 7905. (g) Nakano, H.; Okuyama,
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Y.; Hongo, H. Tetrahedron Lett. 2000, 41, 4615. (h) Pamies, O.; Van
Strijdonck, G. P.; Dieguez, M.; Deerenberg, S.; Net, G.; Ruiz, A.; Claver,
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C.; Kamer, P. C.; van Leeuwen, P. W. N. M. J. Org. Chem. 2001, 66, 8867.
(i) Alexakis, A.; Benhaim, C. Tetrahedron: Asymmetry 2001, 12, 1151.
~ ꢁ ꢁ
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(j) Garcıa Mancheno, O.; Priego, J.; Cabrera, S.; Gomez Arrayas, R.;
Llamas, T.; Carretero, J. C. J. Org. Chem. 2003, 68, 3679. (k) Nakano, H.;
Yokoyama, J.; Okuyama, Y.; Fujita, R.; Hongo, H. Tetrahedron: Asymme-
try 2003, 14, 2361. (l) Tu, T.; Zhou, Y.; Hou, X.; Xin, L.; Dong, X.; Yu, Y.;
Sun, J. Organometallics 2003, 22, 1255. (m) Evans, D. A.; Michael, F. E.;
Tedrow, J. S.; Campos, K. R. J. Am. Chem. Soc. 2003, 125, 3534.
(1) (a) Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vols. I-III. (b) Asymmetric
Catalysis in Organic Synthesis; Noyori, R., Ed.; Wiley: New York, 1994.
(c) Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; VCH: New York, 2000.
(d) Catalytic Asymmetric Synthesis. Acc. Chem. Res. 2000, 33(6) (special issue).
(2) Whitesell, J. K. Chem. Rev. 1989, 89, 1581.
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(n) Verdaguer, X.; Lledo, A.; Lopez-Mosquera, C.; Maestro, M. A.; Pericas,
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M. A.; Riera, A. J. Org. Chem. 2004, 69, 8053. (o) Garcıa Mancheno, O.;
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Gomez Arrayas, R.; Carretero, J. C. J. Am. Chem. Soc. 2004, 126, 456.
(p) Molander, G. A.; Burke, J. P.; Carroll, P. J. J. Org. Chem. 2004, 69, 8062.
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(q) Guimet, E.; Dieguez, M.; Ruiz, A.; Claver, C. Tetrahedron: Asymmetry
(3) (a) Appleton, T. G.; Clark, H. C.; Manzer, L. E. Coord. Chem. Rev.
1973, 10, 335. (b) Murray, S.; Hartley, F. Chem. Rev. 1981, 81, 365.
(4) (a) Lautens, M. A.; Pfaltz, A. Allylic substitution reactions. In Compre-
hensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Heidelberg, 1999; Vol. 2, Chapter 24. (b) For a review of chiral P,N-
ligands, see: Guiry, P. J.; Saunders, C. P. Adv. Synth. Catal. 2004, 346, 497.
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2005, 16, 959. (r) Sola, J.; Reves, M.; Riera, A.; Verdaguer, X. Angew. Chem.,
Int. Ed. 2007, 46, 5020. (s) Cheung, H. Y.; Yu, W.; Lam, F. L.; Au-Yeung,
T. T.-L.; Zhou, Z.; Chan, T. H.; Chan, A. S. C. Org. Lett. 2007, 21, 4295.
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2628 J. Org. Chem. 2010, 75, 2628–2644
Published on Web 03/19/2010
DOI: 10.1021/jo100223w
r
2010 American Chemical Society

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Caldentey and Pericas
JOCArticle
FIGURE 2. Evans’ approach to modular P,S-ligands from enan-
tiopure N-acyloxazolidinones.
SCHEME 1. General Procedure for the Synthesis of Chiral
P,S-Ligands from Epoxy Alcohols 1
FIGURE 1. Highly modular P,S-ligands from epoxy alcohols 1.
catalysis: the sulfur atom in dissymmetrically substituted
thioethers becomes stereogenic upon coordination to the
metal, thus imposing a unique asymmetric environment
close to the reactive metal center.6
In the past several years, we have successfully developed
and fine-tuned families of modular bidentate ligands (N/O,7
N/N,8 S/N,9 P/N,10 P/O-P11) for a variety of enantioselective
processes starting from purely synthetic yet enantiomerically
pure precursors. In the present paper, we report the synthesis
of highly modular P,S-ligands from readily available enantio-
pure arylglycidols (Figure 1).12 An iterative optimization
processinvolvinguptofourstructuralparameters hasallowed
the identification of ligands exhibiting high catalytic activity
and enantioselectivity in the asymmetric substitution of allylic
substrates with a variety of C-, N-, and O-nucleophiles.
It is to be mentioned that the use of chiral epoxides as
starting materials for the modular construction of enantio-
pure P,S-ligands has not been reported in the literature. In a
related approach, Evans et al. reported the desymmetriza-
tion13 of meso-cyclohexene oxide with tert-butyl thiol, fol-
lowed by phosphinylation of the resulting alcohol as an entry
to ligands for the allylic substitution5f and olefin hydrogena-
tion.5m In the same study,5f the preparation of modular
phosphinito thioether ligands was performed from enantio-
pure N-acyloxazolidinones through rather complex sequences
starting with a highly diastereoselective electrophilic halo-
genation andofteninvolving diastereomerseparation, and the
effect of different structural parameters on catalytic activity
and enantioselectivity was analyzed (Figure 2).
SCHEME 2. Two-Step Synthesis of Thioether-Phosphinite
Ligands 4 from Epoxy Ethers 2a
aReagents and conditions: (a) PhSH (2 equiv), NaOH (2 equiv), 65 °C,
20-120 min in dioxane/water (10:1); (b) ClPPh2 (1.1 equiv), NEt3
(1.2 equiv), 10 mol % of DMAP, 20 min in toluene, rt.
In the first step, the primary hydroxy group in the starting
epoxy alcohols (1) is protected, and the resulting epoxy ethers
are then subjected to regio- and stereoespecific ring-opening
by thiolates to afford β-hydroxy sulfides. Treatment of these
intermediates with chlorodiphenylphosphine and triethyla-
mine in the presence of a 10% molar amount of 4-DMAP
affords the desired ligands. Since diphenylphosphinite
units show optimal performance in Pd-catalyzed allylic alky-
lation,5f,q this module was excluded from the optimization
process.
Results and Discussion
For the subsequent evaluation in catalysis, the corres-
ponding π-allylpalladium complexes were generated in situ
from the corresponding P,S-ligand and metal precursor.
Ligand Optimization for the Palladium-Catalyzed Allylic
Alkylation. Optimization of the Ether Moiety. We first inves-
tigated the effect of the steric bulk of the ether moiety OR1 on
the catalytic properties (activity and enantioselectivity) of the
derived π-allylpalladium complexes. The steric environment
at this position has proved to exert a critical influence on the
catalytic activity of other chiral ligands derived from Sharp-
lessepoxy alcoholsina varietyofasymmetric reactions.7,8,10,11
The starting point in our optimization process was trans-
phenylglycidol (1a; Ar = Ph), which is readily available in
enantiopure form by Sharpless epoxidation and can be modified
to incorporate a variety of OR1 groups (Scheme 2). According
to our synthetic plan, epoxy ethers bearing alcohol protecting
groups of increasing sizes (2a-d) were synthesized,7a and then
the regioselective and stereospecific ring-opening of these epoxy
ethers with benzenethiol was studied.
Ligand Design. The general strategy for the synthesis of
these thioether-phosphinite ligands is presented in Scheme 1.
(6) For a reviews of chiral sulfur ligands in asymmetric catalysis, see:
(a) Mellah, M.; Voituriez, A.; Schulz, E. Chem. Rev. 2007, 107, 5133.
(b) Pellissier, H. Tetrahedron 2007, 63, 1297. (c) Bayon, J. C.; Claver, C.;
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Masdeu-Bulto, A. Coord. Chem. Rev. 1999, 193-195, 73. (d) Masdeu-Bulto,
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A.; Dieguez, M.; Martin, E.; Gomez, M. Coord. Chem. Rev. 2003, 242, 159.
(7) (a) Vidal-Ferran, A.; Moyano, A.; Pericas, M. A.; Riera, A. J. Org.
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Chem. 1997, 62, 4970. (b) Pasto, M.; Riera, A.; Pericas, M. A. Eur. J. Org.
Chem. 2002, 2237. (c) Puigjaner, C.; Vidal-Ferran, A.; Moyano, A.; Pericas,
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M. A.; Riera, A. J. Org. Chem. 1999, 64, 7902.
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Jimenez, F.; Muller, G.; Rocamora, M. Chem.;Eur. J. 2002, 8, 4164.
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(8) Pericas, M. A.; Puigjaner, C.; Riera, A.; Vidal-Ferran, A.; Gomez, M.;
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(9) Jimeno, C.; Moyano, A.; Pericas, M. A.; Riera, A. Synlett 2001, 7,
1155.
(10) Popa, D.; Puigjaner, C.; Gomez, M.; Benet-Buchholz, J.; Vidal-Ferran,
ꢁ
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A.; Pericas, M. A. Adv. Synth. Catal. 2007, 349, 2265.
ꢁ
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(11) Fernandez-Perez, H.; Pericas, M. A.; Vidal-Ferran, A. Adv. Synth.
Catal. 2008, 350, 1984.
(12) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1–299.
(13) Iida, T.; Yamamoto, N.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc.
1997, 119, 4783.
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TABLE 1. Yields for the Synthesis of Thioether-Phosphinite
Ligands 4a-d
TABLE 2. Effect of the Steric Bulk in R1 on Conversion and
Enantioselectivity
entry
epoxy ether
yield 3 (%)
yield 4 (%)
overall yield (%)
1
2
3
4
2a
2b
2c
2d
90a
72b
90c
74d
91
82
85
88
82
59
77
65
a20 min. b60 min. c120 min. d120 min, PhSH (5 equiv), NaOH (5 equiv).
One of the most straightforward synthetic procedures for
the ring-opening of epoxides with thiols takes place under
basic conditions in a protic solvent.14 Alternatively, several
ligand
R1
Me
CH2Ph
CHPh2
CPh3
conva (%)
eeb (%)
4a
4b
4c
4d
92
87
>99
>99
12
11
10
12
methods have been reported involving Lewis acid catalysis,
15a
such as the use of catalytic amounts of InCl3
or metal
perchlorate salts in combination with thiols.15b Although the
use of InCl3 or perchlorates has been reported to induce a
completely regioselective ring-opening at the benzylic posi-
tion, a mixture of diastereomers was obtained in our case,
probably via participation of an SN1 mechanism.16 Very
gratifyingly, when phenylglycidyl ethers 2a-d were treated
with sodium benzenethiolate in dioxane-water,14a a com-
pletely regioselective and stereospecific ring-opening took
place. A final phosphinylation led to thioether phosphinites
4a-d, as shown in Scheme 2.
aConversion after 20 min by 1H NMRof the reaction crude. bee values
by chiral HPLC.
TABLE 3. Effect of the Sulfur Substituent on Conversion and
Enantioselectivity
It is interesting to note that the steric effect of R1 has some
influence on the reactivity of the epoxy ethers. For instance,
while the reaction of 2a (R1 = Me) proceeded smoothly
(90% yield) in 20 min (entry 1), 2d (R1 = CPh3) required a
larger excess of thiol (5 equiv) and longer reaction time (2 h)
to achieve a satisfactory conversion (entry 4). The obtained
β-hydroxy sulfides were derivatized with chlorodiphenylphos-
pine in the presence of triethylamine and DMAP following a
well-established procedure for related compounds.17 The
target ligands 4a-d were obtained with overall yields ranging
from 59% to 82% (Table 1) after purification by filtration
through a short pad of silica gel.
Ligands 4a-d were next evaluated in the palladium-
catalyzed asymmetric allylic alkylation (AAA) of 1,3-di-
phenylpropenyl acetate (S1) with dimethyl malonate, using
N,O-bis(trimethylsilyl)acetamide (BSA) as a base.5f The reac-
tions were carried out in dichloromethane at room tempera-
ture in the presence of a catalyst generated in situ from
1.25 mol % of π-allylpalladium chloride dimer, 2.5 mol %
of ligand, and a catalytic amount of KOAc (Table 2).
As clearly shown in Table 2, complete conversions were
observed after 20 min at room temperature for ligands 4c and
4d and almost complete conversion for 4a and 4b. Unfortu-
nately, ligands 4a-d gave the alkylation product with poor
enantioselectivities (10-12% ee) (Table 2).
entry
ligand
R2
conva (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
4e
4f
4g
4h
4i
4j
4k
4l
3,5-dimethylphenyl
2,6-dimethylphenyl
p-methoxyphenyl
p-bromophenyl
p-tert-butylphenyl
2-naphthyl
isopropyl
cyclohexyl
tert-butyl
adamantyl
93
>99
94
>99
>99
88
>99
92
>99
>99
20
43
9
10
15
15
66
71
71
83
4m
4n
aConversion after 20 min by 1H NMRof the reaction crude. bee values
by chiral HPLC.
at convenience for the optimization of the remaining
modules.
Optimization of the Sulfur Substituent. A methyl substitu-
ent was selected as R1 due to the favorable reactivity of the
corresponding epoxy ether toward thiolate ring-opening.
With this restriction, a variety of S-aryl derivatives with
different substitution patterns on the aryl moiety (4e-j) and
S-alkyl derivatives (4k-n) could be easily synthesized fol-
lowing the general synthetic strategy described above
(Scheme 1). Under the standard conditions for the AAA,
we studied the effect of the thioether substituent on the
catalytic performance of ligands 4e-n.
As shown in Table 3, high conversions are observed with
all the studied ligands after 20 min reaction, thus indicating
that the nature of the sulfur substituent does not play any
role on catalytic activity. Concerning enantioselectivity,
changes in the S-substituent showed a remarkably effect,
with bulkier substituents leading to higher enantioselecti-
vities. Thus, among the studied S-aryl substituents, the most
notable improvement in enantioselectivity was observed
Although these results were very disappointing in terms
of enantioselectivity, they provided initial indication that
the steric bulk of R1 has no effect on the stereochemical
outcome of the reaction. Thus, this fragment could be fixed
(14) (a) Takano, S.; Yanase, M.; Ogasawara, K. Heterocycles 1989, 29,
249. (b) Corey, E. J.; Albright, J. O.; Barton, A. E.; Hashimoto, S. J. Am.
Chem. Soc. 1980, 102, 1436.
(15) (a) Yadav, J. S.; Reddy, B. V. S.; Baishya, G. Chem. Lett. 2002, 31,
906. (b) Chini, M.; Crotti, P.; Giovani, E.; Macchia, F.; Pineschi, M. Synlett
1992, 4, 303.
(16) Parker, R. E.; Isaacs, N. S. Chem. Rev. 1959, 59, 737.
(17) (a) Ohe, K.; Morioka, K.; Yonehara, K.; Uemura, S. Tetrahedron:
Asymmetry 2002, 13, 2155. (b) Jia, X.; Li, X.; Lam, W. S.; Kok, S. H. L.; Xu,
L.; Lu, G.; Yeung, C.-H.; Chan, A. S. C. Tetrahedron: Asymmetry 2004, 15,
2273.
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SCHEME 3. Preparation of Ligands Bearing a Mesityl
Substituent
TABLE 4. Effect of the Aryl Substituent on Conversion and
Enantioselectivity
entry
ligand
R2
conva (%)
eeb (%)
1
2
3
7l
7m
7n
cyclohexyl
tert-butyl
adamantyl
96
97
>99
82
87
80
with the bulky 2,6-dimethylphenylthio group (4f, entry 2).
These results provided an indication that bulkier alkyl
thioether substituents could lead to a further increase in
enantioselectivity. In fact, secondary and tertiary S-alkyl
substituents showed a higher enantioselectivity compared
to S-aryl ligands. A much significant increase in the asym-
metric induction was observed in the case of sterically more
demanding groups such as adamantyl and tert-butyl, which
afforded the alkylation product in 83% and 71% ee, respec-
tively (entries 9 and 10).
aConversion after 90 min for ligand 7l and 45 min for ligands 7m,n by
1H NMR of the reaction crude. bee values by chiral HPLC.
SCHEME 4. Synthesis of Ligands 10a and 10ba
As already mentioned, the sulfur atom becomes stereo-
genic upon coordination to the metal, although control of
this new chiral center is not always attainable due to its low
inversion barrier (10-15 kcal/mol).6d,18 In catalytic applica-
tions, this interconversion could have a negative influence on
enantioselectivity due to the presence of competing diaster-
eomeric complexes. We reasoned that sulfur configuration
could be efficiently controlled when a bulky substituent on
sulfur and a bulky aryl substituent are simultaneously pre-
sent on the ligand molecule.5f In line with this notion, we
synthesized analogues of the best ligands prepared so far but
bearing a more sterically demanding mesityl substituent on
the hydrocarbon chain.
aReagents and conditions: (a) 1a: AdSH (2 equiv), NaOH (2 equiv),
dioxane/water, 80 °C, 120 min; 2a: t-BuSH (3 equiv), NaOH (3 equiv),
dioxane/water, 80 °C, 3 h; (b) ClCPh3 (1.2 equiv), pyridine, 90 °C, 18 h;
(c) ClPPh2 (1.1 equiv), NEt3 (1.2 equiv), 10 mol % 4-DMAP, toluene, rt,
40 min.
Optimization of the Skeletal Aryl Substituent. Following
the general synthetic strategy, ligands 7l, 7m, and 7n were
synthesized from the chiral epoxide 1b bearing a mesityl
substituent (Scheme 3).19
complete conversion in 20 min (Table 3). Interestingly, a
positive effect on the enantioselectivity was observed for
ligands 7l and 7m, affording alkylated product P1 in 82%
and 87% ee (entries 1, 2). On the other hand, with ligand 7n
the enantioselectivity decreased slightly (entry 3) compared
with the parent ligand 4n (Ar = Ph) (Table 3, entry 10).
In view of these results, we decided to re-evaluate the
effect of bulkiness on the alkoxy group (OR1) on the best
ligands prepared so far (4n and 7m) in order to seek further
improvement in enantioselectivity. To this end, we planned
to prepare ligands 10a and 10b, conceptually derived from 4n
and 7m and containing a much more sterically demanding
trityloxy substituent (R1 = CPh3).
Unfortunately, the general synthetic strategy employed so
far failed for the preparation of ligands 10a and 10b because
ring-opening of the trityl ethers of 1a and 1b by the required
bulky thiolates could not be accomplished. Alternatively,
ligands 10a and 10b were prepared by a three-step sequence
starting with the thiolate ring-opening of the corresponding
epoxyalcohols (1a, 1b). The so-prepared 3-alkylthio 1,2-diols
8a and 8b, were then submitted to selective protection of the
primary hydroxy group with trityl chloride in pyridine at
90 °C and subsequent phosphinylation of the secondary
alcohol (Scheme 4).
Reaction of the sodium alkoxide of 1b with methyl iodide
allowed the isolation of the expected methyl ether 2f in 93%
yield. β-Hydroxy sulfides 6l-m were obtained by ring-open-
ing with thiolates,14 whereas the β-hydroxy sulfides 4l-n
(Ar = Ph) were obtained in good yields at 65-80 °C in 1 h;
higher temperatures and longer reaction times (4 h for 6l and
20 h for 6m and 6n) were required to achieve the ring-opening
of epoxy ether 2f (Ar = mesityl). Finally, the target ligands
7l-n were readily prepared from β-hydroxy thioethers 6l-n
under the standard phosphinylation conditions (Scheme 3).
Ligands 7l-n were next evaluated in the AAA of S1 (Table 4).
The incorporation of the bulkier mesityl substituent on the
ligand structure provoked a small decrease in the reaction
rate. Thus, nearly complete conversions were achieved in 45
min at room temperature for ligands 7m and 7n (entries 2, 3)
and in 90 min for ligand 7l (entry 1). For comparison, the
corresponding ligands (4l-n) with Ar = phenyl afforded
(18) Abel, E.; Dormer, J.; Ellis, D.; Orrell, K. G.; Sik, V.; Hursthouse,
M. B.; Mazid, M. A. J. Chem. Soc., Dalton Trans. 1992, 1073.
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(19) Medina, E.; Moyano, A.; Pericas, M. A.; Riera, A. Helv. Chim. Acta
2000, 80, 972.
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SCHEME 5. Results obtained in the Pd-catalyzed AAA of S1
SCHEME 6. Thiolate Ring-Opening of Epoxy Ester 11a
with ligands 10a and 10ba
aReagents and conditions: (a) AdSH (3 equiv), NaOH (3 equiv),
dioxane/water, 80 °C, 120 min.
aReaction conditions: 1.25 mol % of [Pd(η3-C3H5)Cl]2, 2.5 mol % of
10a,b, KOAc, dimethyl malonate/BSA (3.0 equiv), CH2Cl2, rt.
SCHEME 7. Synthesis of Ligand 10a-syna
When 10a and 10b were tested in the Pd-catalyzed AAA, we
were pleased to find that this modification in the R1 group had
a positive influence on both catalytic activity and enantio-
selectivity, with 10b leading to the highest enantioselectivity
recorded over the whole optimization process (Scheme 5).
As a final element in our screening, we decided to modify the
relative stereochemistry of the C2/C3 stereogenic centers in the
ligand backbone (Figure 3). It was expected that this modifica-
tion could lead to substantial changes in the conformational
behavior of the 6-membered ring Pd chelate and, hence, to an
increased discrimination between the enantiotopic faces of the
π-allyl system undergoing the substitution reaction.
aReagents and conditions: (a) AdSH (2 equiv), LiOH (2 equiv), dioxane/
water, 80 °C, 60 min; (b) BH3 SMe2 (4 equiv), THF, 16 h; (c) ClCPh3
3
(1.2 equiv), pyridine, 90 °C, 18 h; (d) ClPPh2 (1.1 equiv), NEt3 (1.2 equiv),
10 mol % 4-DMAP, toluene, rt, 40 min.
trans-Glycidic esters and amides are known to undergo
regioselective and stereoespecific opening by thiols, whereas
this process is less reliable with the cis-isomers.24 However, after
some experimentation we found that the use of lithium hydro-
xide instead of sodium hydroxide led to ring-opening of cis-
glycidic ester 11 with complete regioselectivity at the C3 posi-
tion and in a stereoespecific manner (Scheme 7). Interestingly,
crude 12 obtained by this procedure was notably clean, so that
further purification was not required. Reduction of 12 with
borane-dimethyl sulfide complex in THF gave 8a-syn in 85%
yield which was converted uneventfully into 10a-syn.
FIGURE 3. Modification of the relative stereochemistry of C2/C3.
Modification of the Relative Configuration of the Chiral
Centers. The absolute and relative configurations of the two
adjacent functionalized carbons present in the ring-opening
products are determined by the configuration of the starting
epoxide. Thus, starting from the cis-epoxide and following
the general synthetic strategy described in Scheme 1, it
should be possible to obtain the target ligands 10a-syn and
10b-syn; however, highly efficient and enantioselective epox-
idation of cis-cinnamyl alcohol still remains a problem.20-22
As an alternative, we planned to access the enantiopure cis-
epoxy ester through a completely stereodefined approach and
to secure the target syn ligands through a ring-opening plus
reduction sequence. For the implementation of this plan, we
took advantage of the highly enantioselective catalytic dihy-
droxylation (ADH) of inexpensive (E)-methyl cinnamate.
Thus, the 2,3-dihydroxy ester, obtained in high yield and with
an enantiomeric excess >99%, was converted to the cis-
glycidic ester 11 by regioselective tosylation and subsequent
cyclization in basic media with an overall yield of 80%.23
When the ring-opening of the glycidic ester 11 with
adamantanethiol in the presence of sodium hydroxide was
attempted, the process was poorly regioselective leading to a
2.5:1 mixture of regioisomers (Scheme 6).
In order to rationalize the regioselectivity observed in the
ring-opening reaction when lithium hydroxide was used as a
base, a theoretical study was carried out for the two different
pathways of the reaction (attack at C2 or C3). Taking into
account that ester solvolysis likely precedes ring-opening, the
studied reaction system consisted in one molecule of lithium
carboxylate plus one molecule of lithium thiolate. Transition
states (TSs) for the epoxide openings at C2 (TS-C2) and C3
(TS-C3) were located and characterized using DFT calcula-
tions (B3LYP/6-31G (d)). In both TSs (Figure 4), one
lithium cation is simultaneously coordinated to the epoxide
and to one oxygen atom of the carboxylate. The other
lithium cation, in turn, is coordinated to the remaining
oxygen of the carboxylate and to the attacking thiolate. Very
interestingly, in the transition state corresponding to the
ring-opening at C3 (TS-C3) a planar arrangement of the
phenyl group respect to C3 indicates the presence of carbo-
cationic character at that position. This should be reflected in
a very high reactivity toward nucleophilic attack at C3, and
accordingly, a difference of 5.5 kcal mol-1 in favor of the TS
3
leading to the C3 product was found. If the ratio of the
(20) Denis, J. N.; Greene, A. E.; Serra, A. A.; Luche, M.-J. J. Org. Chem.
1986, 51, 46.
(21) Zhang, W.; Basak, A.; Kosugi, Y.; Hoshino, Y.; Yamamoto, H.
Angew. Chem., Int. Ed. 2005, 44, 4389.
(22) Deng, L.; Jacobsen, E. N. J. Org. Chem. 1992, 57, 4320.
(23) Wang, Z.-M.; Kolb, H. C.; Sharpless, K. B. J. Org. Chem. 1994, 59,
5104.
(24) (a) Aggarwal, V. K.; Charmant, J. P. H.; Fuentes, D.; Harvey, J. N.;
Hynd, G.; Ohara, D.; Picoul, W.; Robiette, R.; Smith, C.; Vasse, J. L.; Winn,
C. L. J. Am. Chem. Soc. 2006, 128, 2105. (b) Hashiyama, T.; Inoue, H.;
Konda, M.; Takeda, M. J. Chem. Soc., Perkin Trans. 1 1984, 1725.
(c) Hashiyama, T.; Inoue, H.; Takeda, M. J. Chem. Soc., Perkin Trans. 1
1985, 421.
2632 J. Org. Chem. Vol. 75, No. 8, 2010

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Caldentey and Pericas
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SCHEME 9. Synthesis of Ligand 10b-syna
aReagents and conditions: (a) t-BuSH (3 equiv), LiOH (3 equiv),
dioxane/water, microwave irradiation 140 °C, 3 h; (b) BH3 SMe2
3
(4 equiv), THF, 16 h; (c) ClCPh3 (1.2 equiv), pyridine, 90 °C, 18 h;
(d) ClPPh2 (1.1 equiv), NEt3 (1.2 equiv), 10 mol % of 4-DMAP, toluene,
rt, 40 min.
FIGURE 4. DFT-optimized transition states TS-C3 and TS-C2.
SCHEME 8. Synthesis of Epoxy Ester 17a
TABLE 5. Effect of the Relative Configuration (C2/C3) on Conversion
and Enantioselectivity
entry
ligand
conva (%)
yield (%)
eeb (%)
1
10a-syn
10b-syn
10a-syn
>99
>99
>99
95
97
97
94
96
99
2
3c
aReagents and conditions: (a) see ref 25; (b) ClTs (1.02 equiv), NEt3 (1.5
equiv), CH2Cl2,0°C, 70 h; (c) K2CO3 (3equiv),H2O(5equiv),DMF,rt,24h.
aConversion after 20 min by 1H NMRof the reaction crude. bee values
by chiral HPLC. c0 °C, 240 min.
products follows a Maxwell-Boltzmann distribution based
on the energies of the transition states, the theoretically
computed regioisomeric ratio would be higher than 99:1, in
agreement with the experimental value.
Epoxyester 17, bearing a mesityl substituent, was prepared
from 14 by an analogous sequence (Scheme 8). Probably due
to the presence of unfavorable steric interactions in the
transition state leading to 17, the cyclization of 16 was less
efficient, and the desired epoxy ester 17 was obtained in 63%
yield at 40% conversion (25% yield).
Ring-opening of the rather unreactive epoxy ester 17 could
be induced by performing the reaction under microwave
irradiation at 140 °C in the presence of excess of lithium tert-
butylthiolate (Scheme 9). The resulting carboxylic acid 18
was converted to the target ligand 10b-syn following the
same procedure used for the preparation of 10a-syn.
Ligands 10a-syn and 10b-syn were next evaluated in AAA
of S1 (Table 5).
Again, very high activities were observed for both ligands,
and complete conversions were recorded after 20 min at rt.
Interestingly, a positive effect on the enantioselectivity was
observed with the syn-type ligands, P1 being obtained in
94% and 96% ee with 10a-syn and 10b-syn, respectively. For
comparison, the corresponding ligands with anti-configura-
tion (10a and 10b, Scheme 5) afforded the alkylation product
with 86% and 91% ee, respectively. Very gratifyingly, enan-
tioselectivity increased to 99% with ligand 10a-syn by simply
lowering the reaction temperature to 0 °C, although a some-
what longer reaction time (240 min) was required to achieve
high conversion under these conditions (entry 3).
The synthesis of 10a-syn and 10b-syn completed the mod-
ular optimization of the new family of P,S-ligands. Along
this way, enantioselectivities in the archetypal substitution of
1,3-diphenylallyl acetate with dimethyl malonate have in-
creased from 10 to 12% with 4a-d to 99% with 10a-syn, while
high catalytic activities were observed over the whole series.
To compare the merits of the ligands resulting from
the structural optimization with other well-established P,S-
ligands, we have collected in Figure 5 the enantioselectivities
inthe reaction of S1withdimethylmalonateleading toP1 and
the corresponding reaction conditions for full conversion. It is
interesting to note that the levels of catalytic activity and
enantiocontrol achieved with one of our optimized ligands
(10b-syn) are among the highest recorded in the considered
ligand set. Inparticular, it is worthnoting that10b-syn induces
very high enantioselectivity at room temperature, where the
alkylation is completed in very short reaction times.
Asa finalaspect of thisresearch, the behavior of theoptimal
ligand set (10a,b and 10a,b-syn) was studied in the alkylation
of the more challenging substrates S2 and S3 (Table 6) and in
ꢁ
(25) Ramon, R.; Alonso, M.; Riera, A. Tetrahedron: Asymmetry 2007, 18,
2797.
J. Org. Chem. Vol. 75, No. 8, 2010 2633

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Caldentey and Pericas
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TABLE 7. Effect of the Nucleophile on Conversion and Enantio-
selectivity
entry
ligand
NuH
time (h)
yield (%)
eea (%)
b
1
2
3
4
5
6
7
8
9
10a
10b
BnNH2b
BnNH2b
BnNH2b
BnNH2c
BnNH2
BnOHd
BnOHd
BnOHe
BnOHf
2
16
16
4
10
3
3
16
3
98
73
65
97
95
98
96
55
96
75
73
92
94
95
90
93
86
94
10a-syn
10b-syn
10b-syn
10a-syn
10b-syn
10b-syn
10b-syn
aee values by chiral HPLC. bReaction conditions: 1.25 mol % of
[Pd(η3-C3H5)Cl]2, 3.75 mol % of P,S-ligand, benzylamine (3 equiv),
c
CH2Cl2, rt. Reaction at 0 °C. dReaction conditions: 2 mol % of [Pd-
(η3-C3H5)Cl]2, 4.2 mol % of P,S-ligand, benzyl alcohol (3 equiv),
f
Cs2CO3 (3 equiv), CH2Cl2, rt. eReaction at 0 °C in CH2Cl2. Reaction
at 0 °C in toluene.
FIGURE 5. Behavior of representative P,S-ligands reported in the
literature in the Pd-catalyzed allylic alkylation of 1,3-diphenylpro-
penyl acetate with dimethyl malonate.
effective ones for the allylic substitution of S1, afforded the
alkylation product in much lower enantioselectivities
(entries 3, 4, 7, and 8). Presumably, this lack of enantioselec-
tivity is derived from a different ligand structural require-
ment for the successful alkylation of trisubstituted π-allyl
precurors compared to the disubstituted substrate S1. On the
other hand, using ligands 10a and 10b under standard
conditions for AAA, excellent enantioselectivities were
observed for substrate S2 (96% and 97% ee) and good
asymmetric inductions for substrate S3 (79% and 82% ee;
entries 1, 2, 5 and 6). Interestingly, for substrate S2 and using
ligand 10a, when the reaction was stopped at 54% conver-
sion, the unreacted allylic substrate was recovered in 70% ee
(entry 1), which represents a rather high selectivity for one of
the substrate enantiomers.
TABLE 6. Enantioselective Allylic Alkylation for Substrates S2 and S3
with Dimethyl Malonate
Finally, the optimal set of ligands was also examined in the
palladium-catalyzed reaction of 1,3-diphenylpropenyl acetate
(S1) with different heteroatom nucleophiles. Benzylamine
and benzyl alcohol were chosen as representative models for
N-nucleophiles and O-nucleophiles, respectively, and the
results obtained in these reactions are summarized in Table 7.
The catalytic system involving ligand 10b-syn was found to
be the most effective for the amination and etherification of
S1. After 4 h at rt, the amination product P6 was obtained in
97% yield and 94% ee (entry 4), whereas the analogous
ligand 10b afforded lower yield and enantioselectivity after
16 h (entry 2). Enantioselectivity increased slightly by low-
ering the temperature to 0 °C, but longer reaction time was
required to achieve complete conversion (entry 5). Further-
more, using benzyl alcohol as a nucleophile, 10b-syn was the
most effective ligand for this asymmetric etherification reac-
tion, affording the product P7 in 96% yield and 93% ee after
3 h at rt (entry 7). The same reaction at 0 °C afforded the
product in lower selectivity (86% ee) and lower yield (55%
yield) after 16 h (entry 8). When the solvent was changed to
toluene, the product was obtained in almost quantitative
yield (96%) after 3 h with high enantioselectivity (94% ee)
(entry 9). While numerous examples of enantioselective
allylic amination have been reported, successful examples
entry
ligand
substrate
time (h)
conva (%)
eeb (%)
1
2
3
4
5
6
7
8
10a
10b
10a-syn
10b-syn
10a
10b
10a-syn
10b-syn
S2
S2
S2
S2
S3
S3
S3
S3
16
16
5
54
46
93
92
45
30
99
99
97
96
40
70
79
82
4
5
16
16
5
5
20
aConversion by 1H NMR of the reaction crude. bee values by chiral
HPLC.
the substitution of S1with more challenging nucleophiles such
as benzylamine and benzyl alcohol (Table 7).
Not unexpectedly (see Table 6),26 these trisubstituted
π-allyl precursors proved to be much less reactive in front of
alkylation than the 1,3-diphenyl disubstituted substrate S1.
At room temperature, complete conversion of S2 and S3
was observed over a period of 5 h using ligands 10a,b-syn.
Unfortunately, these ligands, which proved to be the most
(26) (a) Auburn, P. R.; Mackenzie, P. B.; Bosnich, B. J. Am. Chem. Soc.
1985, 107, 2033. (b) Dawson, G. J.; Williams, J. M. J.; Coote, S. J.
Tetrahedron: Asymmetry 1995, 6, 2535. (c) Dawson, G. J.; Williams,
J. M. J.; Coote, S. J. Tetrahedron Lett. 1995, 36, 461.
2634 J. Org. Chem. Vol. 75, No. 8, 2010

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Caldentey and Pericas
JOCArticle
of asymmetric allylic etherification are very scarce. Only a
recent account by Chan et al. reports high enantioselectivi-
ties in this process.5t When both catalytic systems are com-
pared, it is worth mentioning that 10b-syn behaves as a more
active catalyst in the considered reaction while leading to
similar levels of asymmetric induction.
Structural Studies. The binding mode of ligand 10a-syn
was established by X-ray crystallography. A suitable crystal
of the PdCl2 complex of 10a-syn was obtained from dichloro-
methane/diethyl ether. Complex (10a-syn) PdCl2 adopts a
3
twist-boat geometry, and only one epimer of the adamantylthio
substituent is observed in the crystal. In this epimer, the
adamantyl group is in an anti-orientation with respect
1
to the adjacent phenyl group. Furthermore, H NMR and
31P NMR studies on (10a-syn) PdCl2 in CD2Cl2 at rt also
3
showed only one diastereomeric complex, thus indicating that
the sulfur inversion is blocked. In addition, the larger trans
influence of the phosphinite is reflected in the longer Pd-Cl
bond trans to the phosphorus atom (Pd-Cl1 = 2.359 A)
compared to sulfur (Pd-Cl2 = 2.312 A).
Interestingly, a complementary X-ray diffraction study
FIGURE 6. Proposed transition-state models for the asymmetric
allylic substitutions.
performed on 4m PdCl2 showed that changing the relative
3
configuration of the carbons bearing the heteroatoms (C2/C3)
in the ligand backbone leads to a conformational change
of the 6-membered ring Pd-chelate, in agreement with
terminus trans to phosphorus in the M-type complex will
lead to a release of steric congestion between the S-adamantyl
substituent and the proximal phenyl substituent on the allyl
unit, while attack to the corresponding carbon in the W-type
complex will be accompanied by an increasing steric inter-
action between the S-adamantyl group and the corresponding
phenyl group on the allyl moiety as the rotation from the
starting π-allyl complex to the final Pd(0)-olefin product
(R)-P1 proceeds (Figure 6).
previous observations by Evans.5f While complex (10a-syn)
3
PdCl2 showed a twist-boat conformation, crystals of 4m PdCl2
3
grown in dichloromethane/diethyl ether showed a half-chair
conformation in the corresponding six-membered chelate ring
(see Figures 1 and 2 in the Supporting Information).27
Origin of the Enantioselectivity. It has been generally
accepted that the enantiodifferentation step in the Pd-cata-
lyzed allylation is the substitution of π-allyl complexes with
nucleophiles. Two bonds in a trans position compete for
one metal d-orbital for a π-back-bond. The stronger the
π-acceptor ability of the ligand is, the more electronic density
is removed from the metal d-orbital. Through this mechanism,
the electronic density at one of the allylic carbon atoms is
strongly reduced by a π-acceptor in a trans position. Accord-
ingly, nucleophilic attack should occur predominantly at the
allyl terminus located trans to the best π-acceptor (P > S).
Since the (S) enantiomer of the alkylation product is
predominantly obtained, the reaction must proceed through
an M-type rather than W-type intermediate (Figure 6, top).
It can be reasoned from a qualitative perspective that the
M-type complex would react faster than its diastereomer
W-type complex. Thus, attack of the nucleophile to the allyl
Conclusions
In summary, a library of modularly constructed phosphi-
nite thioether ligands derived from the ring-opening of
enantiopure epoxides has been synthesized and evaluated
in the Pd-catalyzed allylic substitution reactions of several
substrates. These P,S-ligands have been successfully opti-
mized by following a modular approach. Over this process,
the enantioselectivity recorded in the benchmark reaction
has evolved from ca. 10% in the initial ligands to 99% in the
optimized structures. In general, activities and enantioselec-
tivities are mainly controlled by the steric interactions be-
tween the substituent on sulfur, and the skeletal aryl group,
and by the relative stereochemistry of the stereocenters at C2
and C3 on the ligand skeleton. Excellent enantioselectivities
were obtained in the reaction of rac-1,3-diphenyl-2-prope-
nylacetate with dimethyl malonate (up to 99%), benzylamine
(up to 95%), and a much less common O-nucleophile,
such as benzyl alcohol (up to 94%). The development of
further applications of these ligands is now in progress in our
laboratories.
(27) Crystal data for 4 m PdCl2 at 100 K: C26H31Cl2O2P1Pd1S1 ꢀ 2 (the
3
unit cell contains two independent molecules), 615.84 gmol-1, triclinic, P1,
a = 10.6012(5) A, b = 12.3725(5) A, c 12.9208(6) A, R = 67.7560(10)°, β =
65.9300(10)°, γ = 65.8490(10)°, V = 1365.60(11) A3, Z = 2, Fcalcd = 1.498
Mg/m3, R1obs= 0.0230 (R1ref = 0.0243), wR2obs = 0.0554 (wR2ref = 0.0561),
for 16893 reflections with I > 2σ(I) (for 17508 reflections (Rint: 0.0227) with a
total of 28395 measured reflections), Flack (std): -0.028(8), diffracting 2θ
range: 3.58-38.13°, goodness-of-fit on F2 = 1.015, largest diff peak (hole) =
1.437 (-0.607) e A-3. CCDC: 755742. Crystal data for (10a-syn) PdCl2 at
3
100 K: C50H49Cl2O2P1Pd1S1, 922.22 gmol-1, orthorhombic, P212121, a =
11.2090(5) A, b = 12.4178(6) A, c 31.5636(15) A, V = 4393.4(4) A3, Z = 4,
Fcalcd = 1.394 Mg/m3, R1obs= 0.0215 (R1ref = 0.0223), wR2obs = 0.0547
(wR2ref = 0.0550), for 24842 reflections with I > 2σ(I) (for 25376 reflections
(Rint: 0.0262) with a total measured of 89664 reflections), Flack (std):
Experimental Section
General Procedure for the Ring-Opening of Epoxides 2a-d by
Thiols. To a solution of the epoxide (1 mmol) and sodium
hydroxide (2 mmol) in dioxane/water (10:1 v/v) was added the
corresponding thiol (2 mmol, 2 equiv). The mixture was heated at
the indicated temperature, and reaction progress was moni-
tored by TLC until disappearance of the starting epoxide
-0.013(6), diffracting 2θ range: 2.77-39.60°, goodness-of-fit on F2
=
1.105, largest diff peak (hole) = 1.539 (-0.456) e A-3.CCDC: 755743. The
supplementary crystallographic data for this paper can be obtained free of
charge from the Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
J. Org. Chem. Vol. 75, No. 8, 2010 2635

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Caldentey and Pericas
JOCArticle
(ca. 20-90 min). The mixture was allowed to reach room temp-
erature. Then, 10 mL of water was added, and the mixture was
extracted with CH2Cl2 (3 ꢀ 15 mL). The combined organic
extracts were dried over Na2SO4. The solvent was removed under
vacuum, and the crude product was purified by flash chroma-
tography on silica gel, eluting with hexane/ethyl acetate mixtures
to give the desired product.
3J = 5.7 Hz, 1H), 4.11-4.17 (m, 1H), 3.28 (dxd, 2J = 9.53 Hz,
3J = 5.76 Hz, 1H), 3.18 (dxd, 2J = 9.53 Hz, 3J = 5.40 Hz, 1H),
2.39 (d, 3J = 5.12 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 143.7,
137.9, 134.6, 131.9, 128.9, 128.8, 128.6, 128.3, 127.8, 127.4, 127.2,
127.1, 87.0, 72.3, 64.9, 56.4; HRMS (ESþ) m/z calcd for
C34H30O2NaS 525.1864 [M þ Na]þ, found 525.1857.
(1R,2S)-1-(3,5-Dimethylphenylthio)-3-methoxy-1-phenylpro-
pan-2-ol (3e). The following reagents were combined in the
amounts indicated according to the general procedure for
the thiolate ring-opening of epoxides and heated at 65 °C for
20 min: 2a (177 mg, 1.078 mmol), 3,5-dimethylbenzenethiol
(326 μL, 2.156 mmol), and NaOH (86.2 mg, 2.156 mmol). The
product was purified by flash chromatography (95% hexane,
5% ethyl acetate) to yield 3e as an oil (270 mg, 83% yield):
[R]26D -204.4 (c 0.7, CHCl3); IR (neat) 3438, 2914, 1599, 1579,
1491, 1451, 1190, 1120, 1074, 962, 847, 748, 699, 686 cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.24-7.38 (m, 5H), 6.97 (s, 2H),
6.85 (s, 1H), 4.33 (d, 3J = 5.85 Hz, 1H), 4.11-4.16 (m, 1H), 3.45
(dxd, 2J = 9.6 Hz, 3J = 4.1 Hz, 1H), 3.4 (dxd, 2J = 9.6 Hz, 3J =
6.1 Hz, 1H), 3.3 (s, 3H), 2.56 (d, 3J = 4.1 Hz, 1H, OH), 2.24 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 138.5, 138.3, 133.5, 129.9,
129.3, 128.8, 128.4, 127.5, 73.9, 71.7, 59.0, 56.1, 21.1; HRMS
(ESþ) m/z calcd for C18H22O2NaS 325.1238 [M þ Na]þ, found
325.1222.
(1R,2S)-3-Methoxy-1-phenyl-1-(phenylthio)propan-2-ol (3a).
The following reagents were combined in the amounts indicated
below, and submitted to the general procedure for the thiolate
ring-opening of epoxides, by performing the reaction at 65 °C
for 20 min: 2a (130 mg, 0.79 mmol), thiophenol (165 μL, 1.58
mmol), and NaOH (63 mg, 1.58 mmol). The product was
purified by flash chromatography (90% hexane, 10% ethyl
acetate) to yield 3a as a white solid (200 mg, 92% yield): mp
90-91 °C; [R]26D -179.4 (c 1.15, CHCl3); IR (neat) 3372, 2891,
1583, 1493, 1481, 1453, 1438, 1348, 1189, 1091, 1073, 1059, 942,
736, 705, 687, 567 cm-1 1H NMR (400 MHz, CDCl3) δ
;
7.19-7.37 (m, 10H), 4.35 (d, 3J = 6.19 Hz, 1H), 4.12-4.17
(m, 1H), 3.40-3.47 (m, 2H), 3.30 (s, 3H), 2.47 (d, 3J = 4.27 Hz,
1H, OH); 13C NMR (100 MHz, CDCl3) δ 138.2, 134.2, 132.3,
128.9, 128.8, 128.4, 127.6, 127.4, 73.8, 71.9, 59.0, 56.2; HRMS
(ESþ) m/z calcd for C16H18O2SNa: 297.0925 [M þ Na]þ, found
297.0936.
(1R,2S)-3-(Benzyloxy)-1-phenyl-1-(phenylthio)propan-2-ol (3b).
The following reagents were combined in the amounts indicated
according to the general thiolate ring-opening of epoxides proce-
dure and heated at 65 °C for 60 min: 2b (111 mg, 0.46 mmol),
thiophenol (96 μL, 0.92 mmol), and NaOH (37 mg, 0.92 mmol).
The product was purified by flash chromatography (95% hexane,
5% ethyl acetate) to yield 3b as a colorless oil (117 mg, 72% yield):
[R]26D -148.7 (c 0.58, CHCl3); IR (neat) 3422, 3058, 3027, 2908,
2861, 1700, 1599, 1582, 1493, 1479, 1204, 1087, 1067, 1025, 736,
(1R,2S)-1-(2,6-Dimethylphenylthio)-3-methoxy-1-phenylpro-
pan-2-ol (3f). The following reagents were combined in the
amounts indicated according to the general procedure fo the
thiolate ring-opening of epoxides and heated at 65 °C for
40 min: 2a (177 mg, 1.078 mmol), 2,6-dimethylbenzenethiol
(326 μL, 2.156 mmol), and NaOH (86.2 mg, 2.156 mmol). The
product was purified by flash chromatography (95% hexane,
5% ethyl acetate) to yield 3f as a white solid (227 mg, 70%
yield): mp 83-84 °C; [R]26D -248.9 (c 0.61, CHCl3); IR (neat)
3457, 2918, 2898, 2888, 2820, 1493, 1457, 1437, 1078, 1063,
1030, 876, 775, 731, 699 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.19-7.25 (m, 5H), 7.01-7.1 (m, 3H), 4.14-4.19 (m, 1H), 3.96
(d, 3J = 6.7 Hz, 1H), 3.51 (dxd, 2J = 9.6 Hz, 3J = 3.8 Hz, 1H),
3.46 (dxd, 2J = 9.6 Hz, 3J = 6.1 Hz, 1H), 3.31 (s, 3H), 2.44 (d,
3J = 4.1 Hz, 1H; OH), 2.36 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 143.5, 138.8, 132.0, 128.6, 128.5, 128.3, 128.1, 127.5,
74.2, 72.1, 59.0, 55.7, 21.9; HRMS (ESþ) m/z calcd for
C18H22O2NaS 325.1238 [M þ Na]þ, found 325.1231.
1
693 cm-1; H NMR (400 MHz, CDCl3) δ 7.19-7.35 (m, 15H),
4.48 (d, 2J = 11.8 Hz, 1H), 4.45 (d, 2J = 11.8 Hz, 1H), 4.37 (d,
3J = 6.15 Hz, 1H), 4.16-4.22 (m, 1H), 3.55 (dxd, 2J = 9.6 Hz,
3J = 2.1 Hz, 1H), 3.54 (dxd, 2J = 9.6 Hz, 3J = 3.3 Hz, 1H), 2.51
(d, 3J = 4.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 138.3, 137.8,
134.3, 132.3, 128.9, 128.4, 127.8, 127.7, 127.6, 127.3, 73.4, 72.0,
71.6, 56.3; HRMS (ESþ) m/z calcd for C22H22O2NaS 373.1238
[M þ Na]þ, found 373.1247.
(1R,2S)-3-(Benzhydryloxy)-1-phenyl-1-(phenylthio)propan-2-
ol (3c). The following reagents were combined in the amounts
indicated according to the general thiolate ring-opening of
epoxides procedure and heated at 65 °C for 120 min: 2c (250 mg,
0.79 mmol), thiophenol (165 μL, 1.58 mmol), and NaOH (63 mg,
1.58 mmol). The product was purified by flash chromatography
(95% hexane, 5% ethyl acetate) to yield 3c as a white solid (305 mg,
(1R,2S)-3-Methoxy-1-(4-methoxyphenylthio)-1-phenylpropan-
2-ol (3g). The following reagents were combined in the amounts
indicated accordingto the generalprocedure for the thiolate ring-
opening of epoxides and heated at 65 °C for 20 min: 2a (115 mg,
0.7 mmol), 4-methoxybenzenethiol (178 μL, 1.4 mmol), and NaOH
(56 mg, 1.4 mmol). The product was purified by flash chromato-
graphy (95% hexane, 5% ethyl acetate) to yield 3g as an oil
90% yield): mp 74-75 °C; [R]26 -117.9 (c 0.51, CHCl3); IR
D
(neat) 3547, 3057, 3025, 2866, 2854, 1596, 1582, 1492, 1470, 1449,
(190 mg, 89% yield): [R]26 -202.8 (c 0.77, CHCl3); IR (neat)
D
1
1338, 1099, 1075, 965, 750, 737, 691, 612 cm-1; H NMR (400
3434, 3060, 2925, 2895, 2835, 1591, 1570, 1492, 1452, 1284, 1243,
1173, 1120, 1028, 1120, 1028, 960, 827, 699, 640 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.21-7.29 (m, 7H), 6.76-6.78 (br t, 1H),
6.74-6.75 (br t, 1H), 4.16 (d, 3J = 6.2 Hz, 1H), 4.09-4.14 (m,
1H), 3.76 (s, 3H), 3.47 (dxd, 2J = 9.6 Hz, 3J = 3.8 Hz, 1H), 3.42
(dxd, 2J = 9.6 Hz, 3J = 6.14 Hz, 1H), 3.3 (s, 3H), 2.53 (d, 3J = 3
.8 Hz, 1H; OH); 13C NMR (100 MHz, CDCl3) δ 159.7, 138.3,
135.7, 128.9, 128.4, 127.5, 124.1, 114.5, 74.1, 71.4, 59.1, 57.5, 55.3;
HRMS (ESþ) m/z calcd for C17H20O3NaS: 327.1031 [M þ Na]þ,
found 327.1044.
3
MHz, CDCl3) δ 7.18-7.33 (m, 20H), 5.3 (s, 1H), 4.41 (d, J =
6.07 Hz, 1H), 4.20-4.25 (m, 1H), 3.54 (d, 3J = 5.2 Hz, 2H), 2.51
3
(d, J = 5.01 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 141.7,
138.3, 134.5, 132.2, 128.9, 128.8, 128.4, 128.4, 128.3, 127.6, 127.5,
127.3, 126.9, 126.9, 84.3, 72.1, 70.4, 56.4; HRMS (ESþ) m/z calcd
for C32H34O2NaS 505.2177 [M þ Na]þ, found 505.2172.
(1R,2S)-1-Phenyl-1-(phenylthio)-3-(trityloxy)propan-2-ol (3d).
The following reagents were combined in the amounts indicated
according to the general thiolate ring-opening of epoxides pro-
cedure and heated at 65 °C for 120 min: 2d (310 mg, 0.79 mmol),
thiophenol (165 μL, 3.95 mmol, 5 equiv), and NaOH (158 mg,
3.95 mmol, 5 equiv). The product was purified by flash chroma-
tography (95% hexane, 5% ethyl acetate) to yield 3d as a white
(1R,2S)-1-(4-Bromophenylthio)-3-methoxy-1-phenylpropan-2-
ol (3h). The following reagents were combined in the amounts
indicated according to the general procedure for the thiolate
ring-opening of epoxides and heated at 65 °C for 30 min: 2a (200mg,
1.218 mmol), 4-bromobenzenethiol (485 mg, 2.436 mmol), and
NaOH (97.4 mg, 2.436 mmol). The product was purified by flash
chromatography (95% hexane, 5% ethyl acetate) to yield 3h as a
solid (293 mg, 74% yield): mp 91-92 °C; [R]26 -70.0 (c 0.65,
D
CHCl3); IR (neat) 3424, 3057, 3026, 2922, 2851, 1596, 1582, 1490,
1448, 1069, 1027, 899,743, 695, 632 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.36-7.39 (m, 6H), 7.18-7.29 (m, 19 H), 4.44 (d,
white solid (350 mg, 81% yield): mp 70-71 °C; [R]26 -207.9
D
2636 J. Org. Chem. Vol. 75, No. 8, 2010

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Caldentey and Pericas
JOCArticle
ethyl acetate) to yield 3l as a white solid (180 mg, 72% yield). Mp
(c 0.81, CHCl3); IR (neat) 3387, 2942, 2904, 2841, 1491, 1468, 1452,
1384, 1371, 1260, 1189, 1091, 1079, 1062, 1007, 994, 944, 875, 817,
790, 732, 727, 698 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.23-7.35
(m, 7H), 7.16 (br s, 1H), 7.14 (br s, 1H), 4.32 (d, 3J = 6.14 Hz, 1H),
4.14 (br m, 1H), 3.39-3.46 (m, 2H), 3.3 (s, 3H), 2.46 (br s, 1H, OH);
13C NMR (100 MHz, CDCl3) δ 137.9, 133.6, 133.5, 131.9, 128.8,
128.5, 127.8, 121.5, 73.7, 72.0, 59.0, 56.2; HRMS (ESþ) m/z calcd
for C16H17O2NaSBr 375.0030 [M þ Na]þ, found 375.0042.
(1R,2S)-1-(4-tert-Butylphenylthio)-3-methoxy-1-phenylpropan-
2-ol (3i). The following reagents were combined in the amounts
indicated according to the general procedure for the thiolate ring-
opening of epoxides and heated at 65 °C for 20 min: 2a (200 mg,
1.218 mmol), 4-tert-butylbenzenethiol (433 μL, 2.436 mmol), and
NaOH (97.4 mg, 2.436 mmol). The product was purified by flash
chromatography (90% hexane, 10% ethyl acetate) to yield 3i as
a white solid (342 mg, 85% yield): mp 71-72 °C; [R]27D -190.5
(c 0.63, CHCl3); IR (neat) 3363, 2951, 2866, 2833, 1493, 1358,
1270, 1195, 1107, 1093, 916, 878, 810, 703, 683 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.24-7.37 (m, 9H), 4.3 (d, 3J = 6.7 Hz, 1H),
4.09-4.14 (m, 1H), 3.42 (dxd, 2J = 9.6 Hz, 3J = 4.1 Hz, 1H), 3.38
(dxd, 2J = 9.6 Hz, 3J = 6 Hz, 1H), 3.28 (s, 3H), 2.56 (d, 3J =
4.1 Hz, OH, 1H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
150.83, 138.3, 132.29, 130.61, 128.84, 128.4, 127.6, 126.0, 73.9,
71.7, 59.0, 56.5, 34.5, 31.2; HRMS (ESþ) m/z calcd for C20H26-
O2S 330.1654 [M], found 330.1656.
68-69 °C; [R]26 -178.4 (c 0.84, CHCl3); IR (neat) 3422, 3056,
D
3028, 2915, 2892, 2847, 2812, 1491, 1449, 1111, 1095, 1074, 1061,
981, 946, 698, 680 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.23-7.39
(m, 5H), 4.03-4.09 (m, 2H), 3.46 (dxd, 2J = 9.6 Hz, 3J = 3.6 Hz,
2
3
1H), 3.41 (dxd, J = 9.6 Hz, J = 5.8 Hz, 1H), 3.35 (s, 3H),
2.43-2.50 (m, 2H), 1.93-1.97 (br d, 1H), 1.54-1.80 (m, 4H),
1.13-1.38 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 139.6, 128.7,
128.4, 127.4, 74.1, 72.7, 59.1, 51.1, 43.3, 33.7, 33.5, 25.9, 25.8, 25.7;
HRMS (ESþ) m/z calcd for C16H24O2NaS: 303.1395 [M þ Na]þ,
found 303.1377.
(1R,2S)-1-(tert-butylthio)-3-methoxy-1-phenylpropan-2-ol (3m).
The following reagents were combined in the amounts indicated
according to the general thiolate ring-opening of epoxides proce-
dure and heated at 75 °C for 1 h: 2a (110 mg, 0.67 mmol), tert-
butylthiol (148 μL, 1.34 mmol) and NaOH (53.6 mg, 1.34 mmol).
The product was purified by flash chromatography (95% hexane,
5% ethyl acetate) to yield 3m as a white solid (115 mg, 71% yield).
Mp 74-75 °C; [R]26 -179.9 (c 0.75, CHCl3); IR (neat) 3445,
D
2962, 2937, 2908, 2860, 2819, 1601, 1490, 1453, 1363, 1264, 1191,
1157, 1117, 1100, 1076, 1062, 986, 940, 743, 698 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.39-7.42 (m, 2H), 7.29-7.33 (m, 2H),
7.22-7.26(m, 1H), 3.99-4.05(m, 2H), 3.36-3.43 (m, 2H), 3.34 (s,
3H), 2.42 (d, 3J= 4.68, 1H, OH), 1.25 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 141.2, 128.8, 128.4, 127.1, 73.8, 73.6, 59.0, 50.7, 44.2, 31.4;
HRMS (ESþ) m/z calcd for C14H22O2NaS: 277.1238 [M þ Na]þ,
found 277.1233.
(1R,2S)-3-Methoxy-1-(naphthalen-2-ylthio)-1-phenylpropan-
2-ol (3j). The following reagents were combined in the amounts
indicated according to the general procedure for the thiolate
ring-opening of epoxides and heated at 65 °C for 20 min: 2a
(200 mg, 1.218 mmol), 2-naphthalenethiol (394 mg, 2.436
mmol), and NaOH (97.4 mg, 2.436 mmol). The product was
purified by flash chromatography (95% hexane, 5% ethyl
acetate) to yield 3j as a white solid (352 mg, 89% yield): mp
85-86 °C; [R]27D -247.3 (c 0.49, CHCl3); IR (neat) 3443, 2924,
2900, 1493, 1469, 1454, 1121, 1105, 1078, 1063, 990, 942, 866,
(1R,2S)-1-(adamantylthio)-3-methoxy-1-phenylpropan-2-ol (3n).
The following reagents were combined in the amounts indicated
according to the general thiolate ring-opening of epoxides proce-
dure and heated at 80 °C for 60 min: 2a (61 mg, 0.37 mmol),
adamanthanethiol (263 mg, 1.48 mmol, 4 equiv) and NaOH
(59.4 mg, 1.48 mmol, 4 equiv). The product was purified by flash
chromatography (90% hexane,10% ethyl acetate) to yield 3n as
a white solid (80 mg, 64% yield). Mp 73-74 °C; [R]26 -176.8
D
816, 751, 730, 696 cm-1; H NMR (400 MHz, CDCl3) δ 7.79
(c 0.96, CHCl3); IR (neat) 3443, 3058, 3025, 2901, 2847, 1599, 1491,
1
1
(br, 1H), 7.74-7.77 (m, 1H), 7.67-7.70 (m, 2H), 7.38-7.47 (m,
5H), 7.22-7.32 (m, 2H), 4.47 (d, 3J = 6.1 Hz, 1H), 4.16-4.31
(m, 1H), 3.47 (dxd, 2J = 9.67 Hz, 3J = 4.4 Hz, 1H), 3.44 (dxd,
1450, 1342, 1299, 1189, 1120, 1042, 963, 747, 698, 666 cm-1; H
NMR (400 MHz, CDCl3) δ 7.39-7.41 (m, 2H), 7.28-7.32 (m,
2H), 7.21-7.26 (m, 1H), 4.11 (d, 3J = 5.97 Hz, 1H), 3.98-4.03 (m,
1H), 3.35-3.41 (m. 2H), 3.32 (s, 3H), 2.50 (d, 3J = 4.68, 1H, OH),
3
3
2J = 9.67 Hz, J = 5.9 Hz, 1H), 3.28 (s, 3H), 2.53 (d, J =
4.4 Hz, 1H; OH); 13C NMR (100 MHz, CDCl3) δ 138.2, 133.5,
132.3, 131.7, 130.9, 129.4, 128.8, 128.5, 128.4, 127.7, 127.6,
127.3, 126.4, 126.2, 73.8, 72.0, 59.0, 56.1; HRMS (ESþ) m/z
calcd for C20H20O2NaS 347.1082 [M þ Na]þ, found 347.1085.
(1R,2S)-1-(isopropylthio)-3-methoxy-1-phenylpropan-2-ol (3k).
The following reagents were combined in the amounts indicated
accordingtothegeneralprocedureforthe thiolatering-opening of
epoxides and heated at 65 °C for 30 min: 2a (215 mg, 1.31 mmol),
2-propanethiol (250 μL, 2.62 mmol) and NaOH (105 mg, 2.62
mmol). The product was purified by flash chromatography (95%
hexane, 5% ethyl acetate) to yield 3k as a white solid (253 mg,
83% yield). Mp 72-73 °C;[R]26D -172.1 (c 0.6, CHCl3);IR(neat)
3438, 2958, 2890, 2862, 2837, 1490, 1462, 1453, 1444, 1246, 1152,
1120, 1062, 1050, 992, 942, 749, 700 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.38-7.41 (m, 2H), 7.31-7.35 (m, 2H), 7.24-7.28 (m,
1H), 4.04-4.09 (m, 1H), 4.02 (d, 3J= 6.4 Hz, 1H), 3.48 (dxd, 2J =
9.6 Hz, 3J = 3.8 Hz, 1H), 3.42 (dxd, 2J = 9.6 Hz, 3J = 6.3 Hz,
1H), 3.36 (s, 3H), 2.66 (sept,3J = 6.7Hz, 1H), 2.41 (br s, 1H, OH),
1.24 (d, 3J = 6.7 Hz, 3H), 1.16 (d, 3J = 6.7 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 139.5, 128.8, 128.5, 127.4, 74.1, 72.7, 59.1,
51.6, 34.7, 23.5, 23.2; HRMS (ESþ) m/z calcd for C13H20O2NaS:
263.1082 [M þ Na]þ, found 263.1084.
1.98 (br s, 3H), 1.75-1.82 (br m, 6H), 1.59-1.67 (br m, 6H); 13
C
NMR (100 MHz, CDCl3) δ 141.6, 128.7, 128.3, 127.0, 73.9, 73.7,
59.0, 48.1, 46.5, 43.8, 36.2, 29.7; HRMS (ESþ) m/z calcd for
C20H28O2NaS: 355.1708 [M þ Na]þ, found 355.1703.
(2S,3R)-3-(adamantylthio)-3-phenylpropane-1,2-diol (8a). The
following reagents were combined in the amounts indicated
according to the general thiolate ring-opening of epoxides pro-
cedure and heated at 80 °C for 120 min: 1a (200 mg, 1.33 mmol),
adamanthanethiol (475 mg, 2.66 mmol) and NaOH (106 mg, 2.66
mmol). The product was purified by flash chromatography (80%
hexane, 20% ethyl acetate) to yield 8a as a white solid (250 mg,
59% yield). Mp 69-70 °C; [R]26 -201.9 (c 0.9, CHCl3); IR
D
(neat) 3402, 2901, 2847, 1598, 1498, 1449, 1341, 1300, 1076, 1042,
1
699 cm-1; H NMR (400 MHz, CDCl3) δ 7.22-7.42 (m, 5H),
4.11 (d, 3J = 6.9 Hz, 1H), 3.86-3.91 (m, 1H), 3.64-3.7 (m. 1H),
3.55-3.6 (m, 1H), 2.37(d, 3J = 5.83 Hz, 1H, OH), 2.04-2.07 (m,
1H, OH), 1.98 (br s, 3H), 1.73-1.85 (br m, 6H), 1.59-1.67 (br m,
6H); 13C NMR (100 MHz, CDCl3) δ 141.5, 128.6, 128.6, 127.2,
74.9, 64.0, 48.2, 46.7, 43.8, 36.1, 29.7; HRMS (ESþ) m/z calcd for
C19H27O2S: 319.1732 [M þ H]þ, found 319.1726.
Selective Protection of the Primary Hydroxyl Group in 8a as a
Trityl Ether. (1R,2S)-1-phenyl-1-(adamantylthio)-3-(trityloxy)-
propan-2-ol (9a). A solution of 8a (235 mg, 0.74 mmol) and
triphenylmethyl chloride (252 mg, 0.89 mmol) in pyridine (6 mL)
was heated at 90 °C for 18 h under N2. The solvent was removed
in vacuo, and the residual oil was chromatographed using
hexane:Et2O (9:1) as eluent to give 283 mg (68%) of 9a as a
white solid. Mp 77-78 °C; [R]26D -79.5 (c 0.9, CHCl3); IR (neat)
(1R,2S)-1-(c yclohexylthio)-3-methoxy-1-phenylpropan-2-ol (3l).
The following reagents were combined in the amounts indicated
according to the general thiolate ring-opening of epoxides procedure
and heated at 65 °C for 20 min: 2a (146 mg, 0.89 mmol), cyclo-
hexylthiol (224 μL, 1.78 mmol) and NaOH (71 mg, 1.78 mmol). The
product was purified by flash chromatography (90% hexane,10%
J. Org. Chem. Vol. 75, No. 8, 2010 2637

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Caldentey and Pericas
JOCArticle
3448, 3083, 3056, 3023, 2901, 2847, 1597, 1490, 1448, 1342, 1299,
1218, 1072, 1042, 1031, 761, 745, 632 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.40-7.43 (m, 6H), 7.14-7.29 (m, 14H), 4.2 (d, 3J =
5.33 Hz, 1H), 4.02-4.07 (m, 1H), 3.14 (dxd, 2J = 9.39 Hz, 3J =
5.57 Hz, 1H), 3.04 (dxd, 2J = 9.39 Hz, 3J = 5.57 Hz, 1H), 2.42
(d, 3J = 6.16, 1H, OH), 1.98 (br s, 3H), 1.72-1.82 (br m, 6H),
1.59-1.68 (br m, 6H); 13C NMR (100 MHz, CDCl3) δ 143.8,
140.9, 128.8, 128.7, 128.1, 127.7, 127.0, 126.7, 86.9, 74.5, 64.9,
48.0, 46.3, 43.9, 36.2, 29.7; HRMS (ESþ) m/z calcd for
C38H40O2NaS: 583.2647 [M þ Na]þ, found 583.2631.
(1R,2S)-1-(Adamanthylthio)-1-mesityl-3-methoxypropan-2-ol
(6n). The following reagents were combined in the amounts
indicated according to the general thiolate ring-opening of
epoxides procedure and heated at 90 °C for 24 h: 2f (100 mg,
0.48 mmol), adamanthanethiol (773 mg, 4.4 mmol, 9 equiv), and
NaOH (175 mg, 4.4 mmol, 9 equiv). The product was purified by
flash chromatography (95% hexane, 5% ethyl acetate) to yield
6n as a white solid (50 mg, 27% yield):mp 87-88 °C; [R]27
D
-149.1 (c 0.58, CHCl3); IR (neat) 3433, 2902, 2848, 1448, 1230,
1113, 1082, 1071, 1043, 948, 899, 851, 608 cm-1
;
1H NMR
3
Protection of epoxyalcohol 1b as a Methyl Ether. (2S,3S)-2-
mesityl-3-(methoxymethyl)oxirane (2f). A solution of 1b (300
mg, 1.56 mmol) in DMF (3 mL) was added via canula to a
suspension of sodium hydride (44 mg, 1.81 mmol) in DMF
(2 mL) at -20 °C under N2. The mixture was stirred for 20 min,
and methyl iodide (126 μL, 2.03 mmol) was syringed into the
mixture. After being stirred for 4 h at -20 °C, the mixture was
allowed to reach room temperature and stirred for another
hour. MeOH (10 mL) and brine (10 mL) were added. The
aqueous solution was extracted with CH2Cl2 (3 ꢀ 20 mL). The
combined organic extracts were dried and concentrated in
vacuo. The residual oil was chromatographed using hexane:
Et2O (9:1-7:3) as eluent to give 300 mg (93%) of the epoxyether
(2f) as an oil. [RD]27 -13.4 (c 0.44, CHCl3); IR (neat) 2977, 2887,
1729, 1615, 1453, 1374, 1315, 1199, 954, 850, 816, 703 cm-1; 1H
NMR (400 MHz, CDCl3) δ 6.82 (s, 2H), 3.88 (dxd, 2J = 11.4 Hz,
(400 MHz, CDCl3) δ 6.82 (s, 1H), 6.79 (s, 1H), 4.45 (d, J =
10.1 Hz, 1H), 4.02-4.08 (m, 1H), 3.82 (dxd, 2J = 9.7 Hz, 3J =
2.6 Hz, 1H), 3.69 (dxd, 2J = 9.7 Hz, 3J = 5.4 Hz, 1H), 3.43 (s,
3H), 2.45 (s, 3H), 2.43 (s, 3H), 2.23 (s, 3H), 2 (br s, 4H),
1.61-1.86 (m, 16H); 13C NMR (100 MHz, CDCl3) δ 137.4,
136.2, 136.1, 135.2, 131.2, 129.2, 74.0, 72.3, 59.1, 46.5, 43.8, 40.8,
36.2, 29.7, 21.7, 21.52, 20.8; HRMS (ESþ) m/z calcd for
C23H34O2NaS 397.2177 [M þ Na]þ, found 397.2177.
(2S,3R)-3-(tert-Butylthio)-3-mesitylpropane-1,2-diol (8b). The
following reagents were combined in the amounts indicated
according to the general thiolate ring-opening of epoxides pro-
cedure and heated at 80 °C for 3 h: 1b (196 mg, 1.02 mmol), tert-
butylthiol (338 μL, 3.06 mmol, 3 equiv), and NaOH (122 mg, 3.06
mmol, 3 equiv). The product was purified by flash chromato-
graphy (hexane/ethyl acetate, 7:3-6:4) to yield 8b as a white
solid (230 mg, 80% yield): mp 103-104 °C; [R]27D -141.3 (c 0.57,
CHCl3); IR (neat) 3347, 2965, 2920, 2861, 1609, 1456, 1363,
1276, 1216, 1162, 1091, 1030, 1012, 918, 878, 849 cm-1; 1H NMR
3
2
3J = 2.9 Hz, 1H), 3.81 (d, J = 2.3 Hz, 1H), 3.56 (dxd, J =
11.4 Hz, 3J = 5.3 Hz, 1H), 3.46 (s, 3H), 3.13-3.16 (m, 1H), 2.35
(s, 6H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 137.4,
137.0, 130.3, 128.6, 72.6, 59.3, 58.3, 54.4, 20.8, 19.6; HRMS
(ESþ) m/z calcd for C13H18O2Na: 229.1204 [M þ Na]þ, found
229.1205.
3
(400 MHz, CDCl3) δ 6.85 (s, 1H), 6.82 (s, 1H), 4.43 (d, J =
10.2 Hz, 1H), 3.97-4.04 (m, 2H), 3.88-3.95 (m, 1H), 2.46 (s, 3H),
2.42 (s, 3H), 2.25 (s, 3H), 2.17-2.22 (br s, 1H, OH), 1.73 (br s,
1H), 1.28 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 137.5, 136.8,
136.7, 134.0, 131.5, 129.4, 73.2, 63.7, 44.9, 31.4, 21.5, 21.5, 20.7;
HRMS (ESþ) m/z calcd for C16H26O2NaS 305.1551 [M þ Na]þ,
found 305.1563.
(1R,2S)-1-(tert-Butylthio)-1-mesityl-3-methoxypropan-2-ol (6m).
The following reagents were combined in the amounts indicated
according to the general thiolate ring-opening of epoxides proce-
dure and heated at 85 °C for 20 h: 2f (21 mg, 0.1 mmol), tert-
butylthiol (98 μL, 0.91 mmol, 9 equiv), and NaOH (37 mg, 0.91
mmol, 9 equiv). The product was purified by flash chromatography
(90% hexane,10% ethyl acetate) to yield 6m as a white solid (20 mg,
65% yield): mp 85-86 °C; [R]26D -102.7 (c 0.64, CHCl3); IR (neat)
3444, 2959, 2921, 2896, 2862, 1611, 1456, 1364, 1161, 1120, 1093,
1061, 931, 850, 823, 728 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.83
(s, 1H), 6.79 (s, 1H), 4.42 (d, 3J = 10.2 Hz, 1H), 4.04-4.09 (m, 1H),
3.81 (dxd, 2J = 9.6 Hz, 3J = 2.5 Hz, 1H), 3.73 (dxd, 2J = 9.6 Hz,
3J=4.9Hz,1H),3.43(s,3H),2.46(s,3H),2.42(s,3H),2.33(s,3H),
1.98 (d, 3J = 3.8 Hz, 1H, OH), 1.27 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 137.4, 136.4, 136.2, 134.8, 131.3, 129.2, 73.9, 72.3, 59.1,
44.3, 43.6, 31.4, 21.5, 20.8; HRMS (ESþ) m/z calcd for C17H28O2-
NaS 319.1708 [M þ Na]þ, found 319.1719.
(1R,2S)-1-(tert-Butylthio)-1-mesityl-3-(trityloxy)propan-2-ol (9b).
A solution of 8b (282 mg, 1 mmol) and triphenylmethyl chloride
(369 mg, 1.3 mmol) in pyridine (7 mL) was heated at 90 °C for 18 h
under N2. The solvent was removed in vacuo, and the residual oil
was chromatographed using hexane/Et2O(9:1-7:1) as eluent to give
350 mg (67%) of 9b as a white solid: mp 109-110 °C; [R]27D -51.7
(c 0.58, CHCl3); IR (neat) 3539, 3057, 3022, 2958, 2921, 1489, 1447,
1363, 1219, 1158, 1091, 1031, 928, 899, 852, 758, 75, 698, 640 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.45-7.5 (m, 5H), 7.22-7.32 (m,
10H), 6.8 (s, 1H), 6.79 (s, 1H), 4.34 (d, 3J = 10 Hz, 1H), 3.99-4.04
(m, 1H), 3.72 (dxd, 2J = 9.7 Hz, 3J = 2.8 Hz, 1H), 3.36 (dxd, 2J =
9.7 Hz, 3J = 5.5 Hz, 1H), 2.43 (s, 3H), 2.39 (s, 3H), 2.23 (s, 3H), 2.12
3
(d, J = 3.8 Hz, 1H, OH), 1.08 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 144.0, 137.5, 136.1, 135.0, 131.2, 129.1, 128.8, 127.8, 127.1,
87.0, 72.6, 65.9, 44.0, 44.0, 31.4, 21.7, 21.5, 20.7; HRMS (ESþ) m/z
calcd for C35H40O2NaS 547.2647 [M þ Na]þ, found 547.2663.
(2R,3R)-3-(Adamantylthio)-2-hydroxy-3-phenylpropanoic acid
(12). A mixture of 11 (200 mg, 1.12 mmol), adamanthanethiol
(398 mg, 2.24 mmol, 2 equiv), and lithium hydroxide (53.8 mg,
2.24 mmol, 2 equiv) in a mixture of dioxane/H2O, 10:1 (4.5 mL)
was stirred at 80 °C for 1 h. Then 10 mL of water was added, and
the mixture was extracted with CH2Cl2 to remove the excess thiol.
The aqueous phasewas acidified withHCl1 Mand extracted with
AcOEt (3 ꢀ 10 mL). The combined organic phases were dried
over MgSO4 and filtered, and the solvent was removed under
reduced pressure. The solid obtained was used without further
purification: mp 197-198 °C; [R]26D -141.27 (c 0.52, CHCl3); IR
(neat) 3435, 3350, 3239, 2922, 2846, 1731, 1692, 1448, 1340, 1096,
698 cm-1;1H NMR(400 MHz, CDCl3) δ7.51 (m, 2H), 7.32-7.36
(m, 2H), 7.24-7.28 (m, 1H), 4.47 (d, 3J = 3.3 Hz, 1H), 4.42 (d,
3J = 3.3 Hz, 1H), 3.11 (s, 1H, OH), 1.98 (br s, 2H), 1.71-1.83 (br
m, 6H), 1.59-1.67 (br m, 6H); 13C NMR (100 MHz, CDCl3) δ
175.0, 141.7, 128.5, 128.3, 127.4, 73.8, 47.9, 46.3, 43.7, 36.1, 29.7;
(1R,2S)-1-(Cyclohexylthio)-1-mesityl-3-methoxypropan-2-ol (6l).
The following reagents were combined in the amounts indicated
according to the general thiolate ring-opening of epoxides proce-
dure and heated at 85 °C for 4 h: 2f (39 mg, 0.19 mmol),
cyclohexylthiol (119 μL, 0.95 mmol, 5 equiv), and NaOH (38 mg,
0.95 mmol, 5 equiv). The product was purified by flash chromato-
graphy (95% hexane, 5% ethyl acetate) to yield 6l as a white solid
(50 mg, 82% yield): mp 89-90 °C; [R]27D -146.8 (c 0.49, CHCl3);
IR (neat) 3447, 2923, 2850, 1447, 1376, 1262, 1195, 1121, 1094,
1063, 851, 643 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.83 (s, 1H),
6.81 (s, 1H), 4.44 (d, 3J = 10.3 Hz, 1H), 4.16-4.22 (m, 1H), 3.82
(dxd, 2J = 9.7 Hz, 3J = 2.3 Hz, 1H), 3.72 (dxd, 2J = 9.7 Hz, 3J =
5 Hz, 1H), 2.52-2.59 (m, 1H), 3.45 (s, 3H), 2.46 (s, 3H), 2.35 (s,
3H), 2.24 (s, 3H), 2-2.07 (m, 1H), 1.94 (d, 3J = 3.9 Hz, 1H, OH),
1.55-1.86 (m, 4H), 1.19-1.39 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 139.2, 136.9, 136.4, 133.7, 131.3, 129.1, 74.2, 72.4, 59.1,
45.0, 44.7, 34.2, 34.0, 26.1, 26.0, 25.7, 21.6, 21.1, 20.7; HRMS (ESþ)
m/z calcd for C19H30O2NaS 345.1864 [M þ Na]þ, found 345.1864.
2638 J. Org. Chem. Vol. 75, No. 8, 2010

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Caldentey and Pericas
JOCArticle
HRMS (ESþ) m/z calcd for C19H24O3NaS 355.1344 [M þ Na]þ,
found 355.1357.
NMR (100 MHz, CDCl3) δ 167.8, 137.3, 136.8, 128.6, 126.9,
61.0, 57.0, 53.4, 20.9, 19.6, 13.6; HRMS (ESþ) m/z calcd for
C14H18O3Na 257.1154 [M þ Na]þ, found 257.1151.
(2R,3R)-3-(Adamantylthio)-3-phenylpropane-1,2-diol (8a-syn).
To a solution of 12 (372 mg, 1.12 mmol) in THF (7 mL) at 0 °C
was added dropwise the complex borane-dimethyl sulfide
(425 μL, 4.48 mmol, 4 equiv), and the mixture was stirred at
rt for 16 h. MeOH was added slowly followed by water. The
mixture was extracted with CH2Cl2 (2 ꢀ 15 mL) and once
with 15 mL of EtOAc. The combined organic phases were dried
with MgSO4 and filtered. The solvent was removed in vacuo to
yield 8a-syn as a white solid (302 mg, 84% yield). The solid
obtained was used without further purification: mp 95-96 °C;
(2R,3R)-3-(tert-Butylthio)-2-hydroxy-3-mesitylpropanoic acid
(18). In a sealed microwave tube were placed the epoxy ester 17
(250 mg, 1.21 mmol), LiOH (87 mg, 3.64 mmol, 3 equiv), and tert-
butylthiol (414 μL, 3.64 mmol) dissolved in 5.5 mL of dioxane/
H2O (10:1). The mixture was stirred at 140 °C under microwave
irradiation for 3 h, 25 mL of water was added, and the mixture
was extracted with CH2Cl2 to remove the excess thiol. The
aqueous phase was acidified with HCl 1 M and was extracted
with AcOEt (3 ꢀ 25 mL). The organic phase was dried with
MgSO4 and filtered, and the solvent was removed in vacuo. 1H
NMR spectrum of the resulting crude showed complete conver-
sion and only one regioisomer. The solid obtained (288 mg, 80%
yield) was used without further purification:mp 127-128 °C;
[R]26D -156.13 (c 0.25, CHCl3); IR (neat) 3547, 2961, 1758, 1702,
[R]26 -240.6 (c 0.32, CHCl3); IR (neat) 3499, 3208, 3053,
D
2898, 2847, 1594, 1108, 1084, 868, 746, 698 cm-1; H NMR
1
3
(400 MHz, CDCl3) δ 7.32-7.2 (m, 5H), 4.07 (d, J = 9.6 Hz,
1H), 3.63-3.55 (m, 2H), 3.45 (s. 1H, OH), 3.31-3.26 (m, 1H),
2.1 (br s, 1H, OH), 2.0 (br s, 3H), 1.77-1.88 (br m, 6H),
1.61-1.69 (br m, 6H); 13C NMR (100 MHz, CDCl3) δ 142.3,
128.6, 128.0, 127.1, 73.7, 62.8, 49.4, 47.1, 43.9, 36.1, 29.7;
HRMS (ESþ) calcd for C19H26O2NaS 341.1551 [M þ Na]þ,
found 341.1548.
1456, 1362, 1162, 1101, 929, 852 cm-1; H NMR (400 MHz,
1
CDCl3) δ 6.83 (s, 1H), 6.8 (s, 1H), 4.62 (d, 3J = 6.8 Hz, 1H), 4.31
(m, 1H), 3.81 (d, 3J = 6.8Hz, 1H), 2.41 (s, 3H), 2.4 (s, 3H), 2.23 (s,
3H), 1.32 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 175.2, 137.3,
136.8, 134.8, 134.5, 131.3, 129.3, 72.2, 47.4, 44.8, 31.4, 21.7, 21.1,
20.8; HRMS (ES-) m/z calcd for C16H23O3S 295.1368 [M - H]-,
found 295.1374.
(1R,2R)-1-(Adamantylthio)-1-phenyl-3-(trityloxy)propan-2-ol
(9a-syn). A solution of 8a-syn (220 mg, 0.7 mmol) and triphenyl-
methyl chloride (235 mg, 0.83 mmol) in pyridine (10 mL) was
heated at 90 °C for 18 h under N2. The solvent was removed in
vacuo, and the residual oil was chromatographed using hexane/
Et2O (9:1-7:1) as eluent to give 300 mg (77%) of 9a-syn as a
white solid: mp 113-114 °C; [R]28D -101.84 (c 0.91, CHCl3); IR
(2R,3R)-3-(tert-Butylthio)-3-mesitylpropane-1,2-diol (8b-syn).
To a solution of 18 (504 mg, 1.7 mmol) in THF (10 mL) at
0 °C was added dropwise 646 μL (44.8 mmol, 4 equiv) of the
complex borane-dimethyl sulfide. The reaction was stirred at rt
for 24 h. Then MeOH was added slowly followed by water. The
mixture was extracted with CH2Cl2 (2 ꢀ 20 mL) and once with
25 mL of EtOAc. The combined organic phases were dried with
MgSO4 and filtered, and the solvent was removed under reduced
pressure. The crude was purified by silica gel chromatography
(hexane/EtOAc) (3:1) to afford 8b-syn (410 mg, 85% yield) as an
(neat) 3461, 2903, 2848, 1489, 1448, 1083, 746, 696 cm-1. H
1
NMR (400 MHz, CDCl3) δ 7.42-7.44 (m, 6H), 7.09-7.27 (m,
14H), 4.3 (d, 3J = 8.5 Hz, 1H), 3.68-3.73 (m, 1H), 3.31 (dxd,
2J = 9.7 Hz, 3J = 3.36 Hz, 1H), 3.16 (d, 3J = 1.75, 1H, OH),
2.72 (dxd, 2J = 9.7 Hz, 3J = 4.1 Hz, 1H), 2.01 (br s, 3H),
1.79-1.9 (br m, 6H), 1.62-1.7 (br m, 6H); 13C NMR (100 MHz,
CDCl3) δ 143.99, 142.8, 128.66, 128.2, 128.09, 127.69, 126.87,
126.61, 86.4, 73.77, 63.79, 49.14, 46.75, 44, 36.19, 29.77; HRMS
(ESþ) m/z calcd for C38H40O2NaS 583.2647 [M þ Na]þ, found
583.2635.
oil: [R]26 -192.9 (c 0.67, CHCl3); IR (neat) 3398, 2959, 2920,
D
1612, 1457, 1365, 1270, 1160, 1093, 1039, 920, 875, 852, 817,
703 cm-1; H NMR (400 MHz, CDCl3) δ 6.81 (s, 2H), 4.4 (d,
1
3J = 10.2 Hz, 1H), 3.77-3.82 (m, 2H), 3.62-3.66 (m, 2H),
3.25-3.31 (m, 1H), 2.46 (s, 3H), 2.34 (s, 3H), 2.23 (s, 3H),
2.12-2.15 (m, 1H), 1.35 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
136.9, 136.4, 135.4, 134.7, 131.1, 129.3, 71.4, 62.7, 47.0, 44.8,
31.6, 21.6, 21.2, 20.7; HRMS (ESþ) m/z calcd for C16H26O2NaS
305.1551 [M þ Na]þ, found 305.1541.
(1R,2S)-1-(Ethoxycarbonyl)-2-hydroxy-2-mesitylethyl 4-Methyl-
benzenesulfonate (16). To a stirred solution of 15 (2.58 g, 10.22
mmol) in 70 mL of DCM at 0 °C under argon was added
triethylamine (2.14 mL, 15.33 mmol, 1.5 equiv) followed by
p-toluenesulfonyl chloride (2 g, 10.43 mmol, 1.02 equiv). After
being stirred for 70 h at 0 °C, the reaction mixture was diluted with
ethyl acetate, and the crude was purified by silica gel chromato-
graphy hexane/AcOEt (7:3) to give 16 as a white solid (3.53 g, 85%
yield): mp 81-82 °C; [R]26D þ17.0 (c 0.22, CHCl3); IR (neat) 3452,
2961, 1704, 1598, 1371, 1310, 1174, 1017, 873, 854 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.78 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz,
2H), 6.74 (s, 2H), 5.38 (dxd, 3J = 7.9 Hz, 3J = 3.8 Hz, 1H), 5.25 (d,
3J = 7.9 Hz, 1H), 3.74-3.86 (m, 2H), 2.47 (d, 3J = 3.8 Hz, 1H,
OH), 2.44 (s, 3H), 2.32 (br s, 6H), 2.2 (s, 3H), 0.84 (t, 3J = 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 166.5, 145.2, 138.1, 137.2,
132.7, 130.2, 129.7, 129.1, 126.2, 80.2, 70.9, 61.6, 21.7, 20.8,
20.6, 13.3; HRMS (ESþ) m/z calcd for C21H26O6NaS 429.1348
[M þ Na]þ, found 429.1337.
(1R,2R)-1-(tert-Butylthio)-1-mesityl-3-(trityloxy)propan-2-ol
(9b-syn). A solution of 8b-syn (430 mg, 1.52 mmol) and triphenyl-
methyl chloride (519 mg, 1.83 mmol) in pyridine (15 mL) was
heated at 90 °C for 24 h under N2. The solvent was removed in
vacuo, and the residual oil was chromatographed using hexane/
Et2O (9:1-7:1) as eluent togive 530mg (66%) of 9b-syn as a white
solid: mp 117-118 °C; [R]27D -110.4 (c 1.01, CHCl3); IR (neat)
3483, 3084, 2959, 1596, 1407, 1112, 929, 852 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.33-7.36 (m, 6H), 7.15-7.23 (m, 9H), 6.71 (s,
1H), 6.6 (s, 1H), 4.27 (d, 3J = 9.6 Hz, 1H), 3.95-4 (m, 1H), 3.48
(s, 1H), 3.11 (dxd, 2J = 9.8 Hz, 3J = 3.4 Hz, 1H), 2.92 (dxd, 2J =
9.8 Hz, 3J = 5.1 Hz, 1H), 2.28 (s, 3H), 2.18 (s, 3H), 2.13 (s, 3H),
1.34 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 143.8, 136.7, 135.9,
135.2, 134.7, 131.0, 129.0, 128.7, 127.6, 126.8, 86.9, 71.6, 65.5,
48.1, 44.4, 31.7, 21.7, 21.4, 20.7; HRMS (ESþ) m/z calcd for
C35H40O2NaS 547.2647 [M þ Na]þ, found 547.2671.
(2S,3S)-Ethyl 3-Mesityloxirane-2-carboxylate (17). A solu-
tion of 16 (3.5 g, 8.61 mmol) and 0.78 mL (43.1 mmol, 5 equiv) of
water in 45 mL of DMF at rt was treated with potassium
carbonate (3.57 g, 25.8 mmol, 3 equiv). After being stirred for
24 h at rt, the reaction mixture was processed with ether in the
usual way, and the crude product was purified by silica gel
chromatography with 10% ether in hexane to provide 0.51 g
(25% yield) of the desired epoxide: [R]27D -13.6 (c 0.42, CHCl3);
IR (neat) 2977, 2923, 1755, 1727, 1613, 1442, 1288, 1188, 1107,
1049, 848 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.76 (s, 2H), 4.22
(d, 3J = 4.4 Hz, 1H), 3.87-4.02 (m, 2H), 3.81 (d, 3J = 4.4 Hz,
General Procedure for the Phosphinite Incorporation. To a
Schlenk flask containing β-hydroxy sulfide (0.55 mmol) and
DMAP (0.055 mmol, 0.1 equiv) in toluene (0.28 M) at rt were
added NEt3 (0.66 mmol, 1.2 equiv) and chlorodiphenylphos-
phine (0.55 mmol, 1.01 equiv) via syringe. The reaction was
stirred for 20 min. The solvent was removed in vacuo, and the
reaction crude was diluted with 95:5 hexane-ethyl acetate
mixture (0.5 mL, dried over molecular sieves, and degassed with
argon). The resulting slurry was loaded onto a plug of silica and
1H), 2.34 (br s, 6H), 2.23 (s, 3H), 0.91 (t, 3J = 7.1 Hz, 3H); 13
C
J. Org. Chem. Vol. 75, No. 8, 2010 2639

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Caldentey and Pericas
JOCArticle
purified by flash chromatography (1 ꢀ 3 cm, 95% hexane, 5%
(m, 1H), 3.14 (dxd, 2J = 9.8Hz, 3J = 5.7Hz, 1H), 3.06 (dxd, 2J =
9.8 Hz, 3J = 5.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 143.7,
142.8 (d, J = 18.5 Hz), 142.1 (d, J = 15.5 Hz), 138.0, 135.5, 131.6,
130.8, 130.6, 130.4, 130.2, 129.4, 129.0, 128.9, 128.7, 128.6, 128.0,
128.0, 127.9, 127.9, 127.7, 127.2, 126.9, 126.8, 87.1, 82.1 (d, J =
19.4 Hz), 64.6 (d, J = 4.2 Hz), 56.1 (d, J = 5.2 Hz); 31P NMR
(162, MHz, CDCl3) δ 118.8; HRMS (ESþ) m/z calcd for
C46H39O2NaSP 709.2306 [M þ Na]þ, found 709.2307.
ethyl acetate).
((1R,2S)-3-Methoxy-1-phenyl-1-(phenylthio)propan-2-yloxy)-
diphenylphosphine (4a). The following reagents were combined
in the amounts indicated according to the general procedure for
the phosphinite incorporation: 3a (151 mg, 0.55 mmol), DMAP
(6.7 mg. 0.055 mmol), NEt3 (92 μL, 0.66 mmol), and chlorodi-
phenylphosphine (101.1 μL, 0.55 mmol). The resulting slurry
was loaded onto a plug of silica and purified by flash chromato-
graphy (1 ꢀ 3 cm, 95% hexane, 5% ethyl acetate) to yield 4a as
((1R,2S)-1-(3,5-Dimethylphenylthio)-3-methoxy-1-phenylpro-
pan-2-yloxy)diphenylphosphine (4e). The following reagents were
combined in the amounts indicated according to the general
procedure for the phosphinite incorporation: 3e (81.7 mg, 0.27
mmol), DMAP (3.3 mg, 0.027 mmol), NEt3 (45 μL, 0.32 mmol),
and chlorodiphenylphosphine (50 μL, 0.27 mmol). The resulting
slurry was loaded onto a plug of silica and purified by flash
chromatography (1 ꢀ 3 cm, 95% hexane, 5% ethyl acetate) to
an oil (230 mg, 91% yield): [R]26 -130.0 (c 0.63, CHCl3); IR
D
(neat) 3067, 2890, 1582, 1492, 1480, 1434, 1127, 1089, 1069,
1024, 998, 965, 953, 739, 691 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.09-7.37 (m, 20H), 4.41-4.46 (m, 2H), 3.37 (dxd, 2J =
9.9 Hz, 3J = 4.44 Hz, 1H), 3.28 (dxd, 2J = 9.9 Hz, 3J = 4.78 Hz,
1H), 2.98 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.1 (d, J =
18.9 Hz), 142.1 (d, J = 14.5 Hz), 138.6, 134.9, 132.2, 130.6,
130.4, 130.4, 130.1, 129.3, 129.0, 128.9, 128.7, 128.1, 128.0,
128.0, 127.9, 127.3, 127.1, 81.5 (d, J = 19.7 Hz), 73.2 (d, J =
3,3 Hz), 58.5, 55.6 (d, J = 6.6 Hz); 31P NMR δ 119.6; HRMS
(ESþ) m/z calcd for C28H27O2NaPS 481.1367 [M þ Na]þ, found
481.1386.
yield 3a as an oil (115 mg, 87% yield): [R]27 -119.8 (c 0.66,
D
CHCl3); IR (neat) 3052, 3027, 2916, 2893, 1599, 1580, 1492, 1480,
1466, 1453, 1434, 1129, 1094, 1074, 1026, 967, 848, 741 cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.41-7.46 (m, 2H), 7.36-7.38 (m,
2H), 7.21-7.33 (m, 11H), 6.91 (s, 2H), 6.81 (s, 1H), 4.47-4.54 (m,
2H), 3.46 (dxd, 2J = 9.9 Hz, 3J = 4.4 Hz, 1H), 3.38 (dxd, 2J =
9.9 Hz, 3J = 4.4 Hz, 1H), 3.06 (s, 3H), 2.21 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ143.3 (d, J= 18.5 Hz), 142.2 (d, J= 14.6 Hz),
138.8, 138.2, 134.3, 130.5 (d, J = 22.0 Hz), 130.2 (d, J = 22.0 Hz),
129.7, 129.3, 129.0, 128.9, 128.8, 128.1, 128.0, 127.9 (d, J = 7.3 Hz),
127.2, 81.5 (d, J = 19.7 Hz), 73.2 (d, J = 3,7 Hz), 58.5, 55.3 (d,
J = 6.5 Hz), 21.1; 31P NMR (162, MHz, CDCl3) δ 119.3; HRMS
(ESþ) m/z calcd for C30H31O2NaPS 509.1680 [M þ Na]þ, found
509.1688.
((1R,2S)-3-(Benzyloxy)-1-phenyl-1-(phenylthio)propan-2-yloxy)-
diphenylphosphine (4b). The following reagents were combined in
the amounts indicated according to the general procedure for the
phosphinite incorporation: 3b (36 mg, 0.1 mmol), DMAP (1.3 mg,
0.01 mmol), NEt3 (17.2 μL, 0.12 mmol), and chlorodiphenylphos-
phine (19 μL, 0.1 mmol). The resulting slurry was loaded onto a
plug of silica and purified by flash chromatography (1 ꢀ 3 cm, 95%
hexane, 5% ethyl acetate) to yield 4b as an oil (45 mg, 82% yield):
[R]26D -117.9 (c 0.51, CHCl3); IR (neat) 3055, 3027, 3002, 2898,
2857, 1582, 1493, 1479, 1434, 1116, 1092, 1070, 1051, 1024, 998, 736,
((1R,2S)-1-(2,6-Dimethylphenylthio)-3-methoxy-1-phenylpro-
pan-2-yloxy)diphenylphosphine (4f). The following reagents were
combined in the amounts indicated according to the general
procedure for the phosphinite incorporation: 3f (87.6 mg, 0.27
mmol), DMAP (3.3 mg, 0.027 mmol), NEt3 (45 μL, 0.32 mmol),
and chlorodiphenylphosphine (50 μL, 0.27 mmol). The resulting
slurry was loaded onto a plug of silica and purified by flash
chromatography (1 ꢀ 3 cm, 95% hexane, 5% ethyl acetate) to
1
691 cm-1; H NMR (400 MHz, CDCl3) δ 7.39-7.43 (m, 2H),
7.13-7.33 (m, 23H), 4.53-4.6 (m, 2H), 4.25 (d, 2J = 11.9 Hz, 1H),
4.21 (d, 2J = 11.9 Hz, 1H), 3.58-3.62 (m, 1H), 3.45-3.49 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 143.0 (d, J = 18.4 Hz), 142.1 (d,
J = 14.7 Hz), 138.6, 137.9, 135.0, 132.1, 130.7, 130.5, 130.4, 129.4,
129.0, 128.9, 128.7, 128.2, 128.1, 128.1, 128.0, 128.0, 127.9, 127.7,
127.5, 127.3, 127.0, 81.6 (d, J = 19.7 Hz), 73.1, 71.0 (d, J =3,6Hz),
55.7; 31P NMR δ 119.1. HRMS (ESþ) m/z calcd for C34H32O2PS
535.1861 [M þ H]þ, found 535.1853.
yield 4f as an oil (110 mg, 80% yield): [R]28 -174.4 (c 0.62,
D
CHCl3); IR (neat) 3052, 2921, 2891, 2859, 2807, 1478, 1457,
1433, 1124, 1106, 1095, 1076, 1060, 1009, 947, 876, 777, 736, 692
((1R,2S)-3-(Benzhydryloxy)-1-phenyl-1-(phenylthio)propan-
2yloxy)diphenylphosphine (4c): [R]27D -59.13 (c 0.44, CHCl3);
IR (neat) 3055, 3027, 3003, 2916, 2857, 1583, 1492, 1479, 1435,
cm-1 1H NMR (400 MHz, CDCl3) δ 7.41-7.45 (m, 2H),
;
7.28-7.32 (m, 3H), 7.11-7.20 (m, 10H), 7.02-7.06 (m, 2H),
3
6.97-6.99 (m, 2H), 4.59-4.66 (m, 1H), 4.15 (d, J = 6.7 Hz,
1
1091, 1071, 1047, 1025, 1000, 923, 740, 693 cm-1; H NMR
1H), 3.49 (dxd, 2J = 10 Hz, 3J = 4.98 Hz, 1H), 3.43 (dxd, 2J =
10 Hz, 3J = 4.4 Hz, 1H), 3.03 (s, 3H), 2.28 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 143.6, 143.2 (d, J = 19 Hz), 142.1 (d, J =
14 Hz), 139.5, 132.6, 130.4 (d, J = 19.1 Hz), 130.2 (d, J =
18 Hz), 129.0, 129.0, 128.6, 128.3, 128.1, 128.0 (d, J = 7.3 Hz),
128.0, 127.8 (d, J = 7 Hz), 127.0, 82.4 (d, J = 19.7 Hz), 73.6 (d,
J = 2.93 Hz), 58.4, 55.4 (d, J = 6.56 Hz), 21.9; 31P NMR (162,
MHz, CDCl3) δ 120.4; HRMS (ESþ) m/z calcd for C30H31O2N-
aPS 509.1680 [M þ Na]þ, found 509.1683.
(400 MHz, CDCl3) δ 7.26-7.30 (m, 2H), 7.06-7.19 (m, 28H),
5.02 (s, 1H), 4.46-4.55 (m, 2H), 3.54 (dxd, 2J = 10.2 Hz, 3J =
4.8 Hz, 1H), 3.40 (dxd, 2J = 10.2 Hz, 3J = 5.16 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) δ 142.8 (d, J = 18.3 Hz), 142 (d, J =
15.23 Hz), 141.94, 141.91, 138.6, 134.99, 132.03, 130.68,
130.47, 130.38, 130.16, 129.4, 129.97, 128.93, 128.72, 128.25,
128.2, 128.08, 128.03, 128.0, 127.98, 127.91, 127.34, 127.27,
127.21, 126.98, 126.87, 84.15, 81.73 (d, J = 19.81 Hz), 69.63 (d,
J = 3,78 Hz), 58.56, 57.72 (d, J = 6.03 Hz); 31P NMR (162,
MHz, CDCl3) δ 118.38; HRMS (ESþ) m/z calcd for
((1R,2S)-3-Methoxy-1-(4-methoxyphenylthio)-1-phenylpropan-
2-yloxy)diphenylphosphine (4g). The following reagents were
combined in the amounts indicated according to the general
procedure for the phosphinite incorporation: 3g (82.2 mg, 0.27
mmol), DMAP (3.3 mg, 0.027 mmol), NEt3 (45 μL, 0.32 mmol),
and chlorodiphenylphosphine (50 μL, 0.27 mmol). The resulting
slurry was loaded onto a plug of silica and purified by flash
chromatography (1 ꢀ 3 cm, 95% hexane, 5% ethyl acetate) to
C
40H35O2NaSP: 633.1993 [M þ Na]þ, found 633.2010.
Diphenyl((1R,2S)-1-phenyl-1-(phenylthio)-3-(trityloxy)propan-
2-yloxy)phosphine (4d). The following reagents were combined in
the amounts indicated according to the general procedure for
the phosphinite incorporation: 3d (85.6 mg, 0.17 mmol), DMAP
(2.1mg, 0.017mmol),NEt3 (29μL, 0.2 mmol), and chlorodiphenyl-
phosphine (31.5 μL, 0.17 mmol). The resulting slurry was loaded
onto a plug of silica and purified by flash chromatography (1 ꢀ
3 cm, 95% hexane, 5% ethyl acetate) to yield 4d as an oil (103 mg,
88% yield): [R]25D -56.7 (c 0.67, CHCl3); IR (neat) 3056, 3025,
3004, 2922, 2872, 2852, 1583, 1491, 1480, 1448, 1436, 1218,
yield 3a as an oil (112 mg, 85% yield): [R]27 -93.7 (c 0.65,
D
CHCl3); IR (neat) 2924, 2893, 2835, 1591, 1571, 1493, 1454, 1438,
1
1285, 1246, 1181, 1126, 1104, 1072, 720, 640 cm-1; H NMR
(400 MHz, CDCl3) δ 7.33-7.37 (m, 2H), 7.12-7.22 (m, 15H),
3
6.64-6.66 (m, 2H), 4.38-4.44 (m, 1H), 4.26 (d, J = 5.85 Hz,
1
2
3
1072, 1026, 1000, 747, 696 cm-1; H NMR (400 MHz, CDCl3)
1H), 3.68 (s, 3H), 3.38 (dxd, J = 9.8 Hz, J = 5.26 Hz, 1H),
3.31 (dxd, 2J = 9.8 Hz, 3J = 4.82 Hz, 1H), 2.97 (s, 3H); 13C NMR
3
δ 7.01-7.30 (m, 35H), 4.50 (d, J = 4.98 Hz, 1H), 4.39-4.45
2640 J. Org. Chem. Vol. 75, No. 8, 2010

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Caldentey and Pericas
JOCArticle
(100 MHz, CDCl3) δ 159.6, 143.3 (d, J = 19 Hz), 142.3 (d, J =
14 Hz), 138.8, 135.6, 130.5, 130.4, 130.3, 130.2, 129.4, 129.0, 128.8,
128.1, 128.0, 128.0, 127.9, 127.9, 127.1, 124.9, 114.3, 81.2 (d, J =
((1R,2S)-1-(Isopropylthio)-3-methoxy-1-phenylpropan-2-yloxy)-
diphenylphosphine (4k). The following reagents were combined in
the amounts indicated according to the general procedure for
the phosphinite incorporation: 3k (64.9 mg, 0.27 mmol), DMAP
(3.3 mg, 0.027 mmol), NEt3 (45 μL, 0.32 mmol), and chlorodi-
phenylphosphine (50 μL, 0.27 mmol). The resulting slurry was
loaded onto a plug of silica and purified by flash chromatography
(1 ꢀ 3 cm, 95% hexane, 5% ethyl acetate) to yield 4k as an oil
(99 mg, 86% yield): [R]28D -106.9 (c 0.58, CHCl3); IR (neat) 3160,
3139, 3125, 2957, 1738, 1492, 1480, 1453, 1434, 1381, 1365, 1230,
1216, 1200, 1130, 1095, 1073, 1054, 1026, 760, 741, 699 cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.40-7.48 (m, 4H), 7.16-7.34 (m,
19.3 Hz), 73.4 (d, J = 3 Hz), 58.5, 56.9 (d, J = 6.56 Hz), 52.2; 31
P
NMR (162, MHz, CDCl3) δ 119.4; HRMS (ESþ) m/z calcd for
C29H30O3PS 489.1653 [M þ H]þ, found 489.1652.
((1R,2S)-1-(4-Bromophenylthio)-3-methoxy-1-phenylpropan-
2-yloxy)diphenylphosphine (4h). The following reagents were
combined in the amounts indicated according to the general
procedure for the phosphinite incorporation: 3h (95.4 mg, 0.27
mmol), DMAP (3.3 mg, 0.027 mmol), NEt3 (45 μL, 0.32 mmol),
and chlorodiphenylphosphine (50 μL, 0.27 mmol). The result-
ing slurry was loaded onto a plug of silica and purified by flash
chromatography (1 ꢀ 3 cm, 95% hexane, 5% ethyl acetate) to
3
11H), 4.41-4.48 (m, 1H), 4.24 (d, J = 6.7 Hz, 1H), 3.55 (dxd,
2J = 10.23 Hz, 3J = 4.97 Hz, 1H), 3.47 (dxd, 2J = 10.23 Hz, 3J =
yield 4h as an oil (129 mg, 89% yield): [R]27 -100.6 (c 0.31,
3
4.38 Hz, 1H), 3.17 (s, 3H), 2.63-2.73 (sept, J = 6.7 Hz, 1H),
D
1.24 (d, 3J = 6.7 Hz, 3H), 1.16 (d, 3J = 6.7 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 143.2 (d, J = 19 Hz), 142.1 (d, J = 14 Hz),
140.0, 130.5, 130.4, 130.3, 130.2, 129.2, 128.9, 128.7, 128.1, 128.0,
128.0, 127.8, 127.8, 127.0, 82.4 (d, J = 19 Hz), 73.3 (d, J =
3,42 Hz), 58.6, 50.6 (d, J= 5.8 Hz), 34.7, 23.4, 23.2; 31P NMR (162,
MHz, CDCl3) δ 119.2; HRMS (ESþ) m/z calcd for C25H29O2P-
NaS 447.1524 [M þ Na]þ, found 447.1517.
CHCl3); IR (neat) 3053, 2891, 1492, 1472, 1453, 1385, 1231,
1190, 1129, 1091, 1070, 1026, 1009, 887, 741, 698 cm-1 1H
;
NMR (400 MHz, CDCl3) δ 7.32-7.36 (m, 2H), 7.14-7.27 (m,
15H), 7.01-7.05 (m, 2H), 4.34-4.44 (m, 2H), 3.36 (dxd, 2J =
9.8 Hz, 3J = 4.5 Hz, 1H), 3.23 (dxd, 2J = 9.8 Hz, 3J = 5.11 Hz,
1H), 3.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.0 (d, J =
18.9 Hz), 142.0 (d, J = 15.5 Hz), 138.1, 134.1, 133.6, 131.8,
130.7, 130.5, 130.3, 130.1, 129.4, 129.1, 129.0, 128.2, 128.1,
128.1, 128.1, 128.0, 127.5, 121.3, 81.2 (d, J = 19.7 Hz), 73.0 (d,
J = 3,6 Hz), 58.6, 55.7 (d, J = 5.9 Hz); 31P NMR (162, MHz,
CDCl3) δ 119.4; HRMS (ESþ) m/z calcd for C28H27O2PBrS
537.0653 [M þ H]þ, found 537.0634.
((1R,2S)-1-(Cyclohexylthio)-3-methoxy-1-phenylpropan-2-yloxy)-
diphenylphosphine (4l). The following reagents were combined in
the amounts indicated according to the general procedure for
the phosphinite incorporation: 3l (31 mg, 0.11 mmol), DMAP
(1.4 mg, 0.011 mmol), NEt3 (19 μL, 0.13 mmol), and chlorodi-
phenylphosphine (20 μL, 0.11 mmol). The resulting slurry was
loaded onto a plug of silica and purified by flash chromatography
(1 ꢀ 3 cm, 95% hexane, 5% ethyl acetate) to yield 4l as an oil
(35mg, 68%yield):[R]28D -104.9 (c0.54, CHCl3);IR(neat) 2924,
2850, 1492, 1480, 1449, 1435, 1129, 1096, 1070, 927, 885, 741,
697 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.14-7.46 (m, 15H),
4.38-4.44 (m, 1H), 4.23 (d, 3J = 6.72 Hz, 1H), 3.54 (dxd, 2J =
10 Hz, 3J = 6.72 Hz, 1H), 3.44 (dxd, 2J = 10 Hz, 3J = 4.4 Hz,
1H), 3.14 (s, 3H), 2.42-2.50 (m, 1H), 1.92-1.95 (br d, 1H),
1.63-1.79 (m, 4H), 1.14-1.32 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 143.2 (d, J = 18.3 Hz), 142.1 (d, J = 14.54 Hz), 140.2,
130.5, 130.4, 130.3, 130.2, 129.1, 129.0, 128.7, 128.2, 128.0, 128.0,
127.9, 127.8, 127.0, 82.6 (d, J = 19 Hz), 73.4 (d, J = 3,3 Hz), 58.6,
50.0 (d, J = 6.6 Hz), 43.3, 33.5, 29.7, 26.0, 25.8, 25.8; 31P NMR
(162, MHz, CDCl3) δ 119.0; HRMS (ESþ) m/z calcd for
C28H33O2NaPS 487.1837 [M þ Na]þ, found 487.1830.
((1R,2S)-1-(4-tert-Butylphenylthio)-3-methoxy-1-phenylpropan-
2-yloxy)diphenylphosphine (4i). The following reagents were com-
bined in the amounts indicated according to the general procedure
for the phosphinite incorporation: 3i (86 mg, 0.26 mmol), DMAP
(3.2 mg, 0.026 mmol), NEt3 (44 μL, 0.31 mmol), and chlorodi-
phenylphosphine (48 μL, 0.26 mmol). The resulting slurry was
loaded onto a plug of silica and purified by flash chromatography
(1ꢀ 3 cm, 95% hexane, 5% ethyl acetate) to yield 4i as an oil (107 mg,
80% yield): [R]26 -103.6 (c 0.61, CHCl3); IR (neat) 3053, 2959,
D
1491, 1481, 1452, 1434, 1394, 1362, 1190, 1128, 1120, 1073, 741,
1
697 cm-1; H NMR (400 MHz, CDCl3) δ 7.21-7.44 (m, 19H),
4.45-4.53 (m, 2H), 3.42 (dxd, 2J = 9.9 Hz, 3J = 5.3 Hz, 1H), 3.35
(dxd, 2J = 9.9 Hz, 3J = 4.84 Hz, 1H), 3.02 (s, 3H), 1.26 (s, 9H); 13
C
NMR (100 MHz, CDCl3) δ 150.4, 143.2 (d, J = 18.3 Hz), 142.2 (d,
J = 14.3 Hz), 138.9, 132.2, 131.4, 130.6, 130.4, 130.4, 130.2, 129.3,
129.0, 128.5, 128.1, 128.1, 128.0, 128.0, 127.9, 127.2, 125.8, 81.5 (d,
J = 19.6 Hz), 73.3 (d, J = 3,1 Hz), 58.5, 55.8 (d, J = 6.7 Hz), 34.5,
31.2; 31PNMR(162,MHz,CDCl3) δ119.3; HRMS (ESþ) m/zcalcd
for C32H35O2NaSP 537.1993 [M þ Na]þ, found 537.2002.
((1R,2S)-1-(tert-Butylthio)-3-methoxy-1-phenylpropan-2-yloxy)-
diphenylphosphine (4m). The following reagents were combined in
the amounts indicated according to the general procedure for
the phosphinite incorporation: 3m (53.4 mg, 0.21 mmol), DMAP
(2.6 mg, 0.021 mmol), NEt3 (35 μL, 0.25 mmol), and chlorodi-
phenylphosphine (39 μL, 0.21 mmol). The resulting slurry was
loaded onto a plug of silica and purified by flash chromatography
(1 ꢀ 3 cm, 95% hexane, 5% ethyl acetate) to yield 4m as an oil
(84 mg, 91% yield): [R]27D -116.6 (c 0.63, CHCl3); IR (neat) 3056,
3000, 2960, 2938, 2895, 1492, 1480, 1471, 1453, 1437, 1364, 1189,
((1R,2S)-3-Methoxy-1-(naphthalen-2-ylthio)-1-phenylpropan-
2-yloxy)diphenylphosphine (4j). The following reagents were
combined in the amounts indicated according to the general
procedure for the phosphinite incorporation: 3j (87.6 mg, 0.27
mmol), DMAP (3.3 mg, 0.027 mmol), NEt3 (45 μL, 0.32 mmol),
and chlorodiphenylphosphine (50 μL, 0.27 mmol). The resulting
slurry was loaded onto a plug of silica and purified by flash
chromatography (1 ꢀ 3 cm, 95% hexane, 5% ethyl acetate) to
1
1127, 699 cm-1; H NMR (400 MHz, CDCl3) δ 7.16-7.44 (m,
yield 4j as an oil (110 mg, 80% yield): [R]27 -52.2 (c 0.42,
15H), 4.32-4.39 (m, 1H), 4.19 (d, J = 6.4 Hz, 1H), 3.49 (dxd,
3
D
3
2
3
CHCl3); IR (neat) 3053, 2922, 2890, 2858, 1588, 1493, 1453,
1437, 1227, 1194, 1125, 1114, 965, 943, 744, 728, 695 cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.74-7.78 (m, 2H), 7.65-7.69 (m,
2H), 7.20-7.47 (m, 18H), 4.68 (d, 3J = 5.9 Hz, 1H), 4.54-4.60
2J = 9.7 Hz, J = 4.97 Hz, 1H), 3.32 (dxd, J = 9.7 Hz, J =
5.1 Hz, 1H), 3.13 (s, 3H), 1.21 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 143.3 (d, J = 19 Hz), 142.1 (d, J = 14 Hz), 141.9, 130.5
(d, J = 13.8 Hz), 130.355 (d, J = 15 Hz), 129.452, 129.0, 128.7,
128.0, 128.0, 127.8 (d, J = 6.8 Hz), 126.7, 83.3 (d, J = 19 Hz), 73.0
(d, J = 3.75 Hz), 58.5, 49.2 (d, J = 5.8 Hz), 44.2, 31.3; 31P NMR
(162, MHz, CDCl3) δ 118.7; HRMS (ESþ) m/z calcd for C26H31-
O2PNaS 461.1680 [M þ Na]þ, found 461.1682.
2
3
(m, 1H), 3.50 (dxd, J = 9.9 Hz, J = 5.5 Hz, 1H), 3.4 (dxd,
2J = 9.9 Hz, 3J = 5.3 Hz, 1H), 3.07 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 143.1 (d, J = 18.3 Hz), 142.1 (d, J = 14.6 Hz), 138.5,
133.6, 132.4, 132.2, 130.7, 130.5, 130.3, 130.1, 129.4, 129.4, 129.0,
129.0, 128.2, 128.2, 128.1, 128.0, 128.0, 127.9, 127.6, 127.4, 127.4,
126.3, 126.0, 81.4 (d, J = 19.76 Hz), 73.1 (d, J = 3,7 Hz),
58.6, 55.4 (d, J = 6.2 Hz); 31P NMR (162, MHz, CDCl3) δ
119.6; HRMS (ESþ) m/z calcd for C32H29O2NaPS 531.1524
[M þ Na]þ, found 531.1523.
4m PdCl2. To a Schlenk flask containing the thiophosphinite
3
ligand 4m (2.02 mg, 0.0046 mmol) in CH2Cl2 (0.1 mL) was
added (MeCN)2PdCl2 (1.19 mg 0.0046 mmol), and the reaction
was stirred for 30 min. The solution was concentrated in vacuo,
and the residue diluted with CH2Cl2 (0.1 mL). Et2O (1.1 mL)
J. Org. Chem. Vol. 75, No. 8, 2010 2641

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Caldentey and Pericas
JOCArticle
was then added rapidly with stirring to precipitate 4m PdCl2,
(d, J = 3.1 Hz), 58.5, 45.1, 43.9 (d, J = 5.9 Hz), 34.3, 33.8, 26.2,
26.1, 25.8, 21.7, 21.3 (d, J = 2.2 Hz), 20.8; 31P NMR (162, MHz,
CDCl3) δ 117.3; HRMS (ESþ) m/z calcd for C31H40O2PS:
507.2487 [M þ H]þ, found 507.2506.
3
which was filtered and dried in vacuo overnight. An X-ray
quality crystal was obtained by slow diffusion of Et2O into a
solution of 4m PdCl2 in CH2Cl2.
3
((1R,2S)-1-(Adamantylthio)-3-methoxy-1-phenylpropan-2-yloxy)-
diphenylphosphine (4n). The following reagents were combined in
the amounts indicated according to the general procedure for
the phosphinite incorporation: 3n (37 mg, 0.11 mmol), DMAP
(1.3 mg, 0.011 mmol), NEt3 (19 μL, 0.13 mmol), and chlorodi-
phenylphosphine (20 μL, 0.11 mmol). The resulting slurry was
loaded onto a plug of silica and purified by flash chromatography
(1 ꢀ 3 cm, 95% hexane, 5% ethyl acetate) to yield 4n as an oil
(45mg, 78%yield):[R]28D -129.7 (c 0.49, CHCl3);IR(neat) 2901,
2847, 1492, 1480, 1450, 1434, 1343, 1300, 1128, 1095, 1071, 966,
((1R,2S)-1-(tert-Butylthio)-1-mesityl-3-methoxypropan-2-yloxy)-
diphenylphosphine (7m). The following reagents were combined in
the amounts indicated according to the general procedure for
the phosphinite incorporation: 6m (26.7 mg, 0.09 mmol), DMAP
(1.1 mg, 0.009 mmol), NEt3 (15 μL, 0.11 mmol), and chlorodi-
phenylphosphine (17 μL, 0.09 mmol). The resulting slurry was
loaded onto a plug of silica and purified by flash chromatography
(1 ꢀ 3 cm, 95% hexane, 5% ethyl acetate) to yield 7m as an oil
(39 mg, 90% yield): [R]25 = -23.4 (c 0.58, CHCl3); IR (neat)
D
2920, 2894, 2861, 1479, 1470, 1457, 1435, 1126, 1093, 1068, 1054,
1028, 1000, 967, 947, 739, 697 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.39-7.44 (m, 2H), 7.25-7.31 (m, 3H), 7.09-7.13 (m, 1H),
6.96-7 (m, 2H), 6-6.64 (m, 4H), 4.6 (d, 3J = 11 Hz, 1H), 4.33-4
(m, 1H), 3.8-3.86 (m, 2H), 3.14 (s, 3H), 2.37 (s, 3H), 2.36 (s, 3H),
2.20 (s, 3H), 1.26 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 143.8,
(d, J = 18.3 Hz), 142.2 (d, J = 13.2 Hz), 137.0, 136.2, 136.2,
135.4, 131.0, 130.0 (d, J = 22 Hz), 128.9, 128.7, 128.2, 127.9 (d,
J = 7.0 Hz), 127.4 (d, J = 6.6 Hz), 81.9 (d, J = 19.8 Hz), 73.3 (d,
J = 2.85 Hz), 58.4, 44.6, 42.7 (d, J = 6.5 Hz), 31.3, 21.5 (d, J =
2.7 Hz), 20.8; 31P NMR (162, MHz, CDCl3) δ 117.8; HRMS
(ESþ) m/z calcd for C29H38O2PS 481.2330 [M þ H]þ, found
481.2314.
945, 924, 751, 694 cm-1 1H NMR (400 MHz, CDCl3) δ
;
7.36-7.44 (m, 4H), 7.14-7.31 (m, 14H), 4.30-4.36 (m, 1H),
4.26 (d, 3J = 6.31 Hz, 1H), 3.50 (dxd, 2J = 9.8 Hz, 3J = 5.01 Hz,
1H), 3.33 (dxd, 2J = 9.8 Hz, 3J = 5.02 Hz, 1H), 3.12 (s, 3H), 1.94
(br s, 3H), 1.71-1.81 (brm, 6H), 1.57-1.64 (br m, 6H); 13C NMR
(100 MHz, CDCl3) δ 143.3 (d, J = 19.3 Hz), 142.4, 142.2 (d, J =
13.9 Hz), 130.6, 130.5, 130.4, 130.2, 129.3, 129.0, 128.7, 128.0,
128.0, 128.0, 127.8, 126.6, 83.6 (d, J = 19 Hz), 73.1 (d, J =
3,3 Hz), 58.5, 46.5(d, J = 6.5 Hz), 43.7, 43.7, 36.2, 29.7; 31P NMR
(162, MHz, CDCl3) δ 118.7; HRMS (ESþ) m/z calcd for
C32H38O2PS: 517.2330 [M þ H]þ, found 517.2302.
((1R,2S)-1-(Adamantylthio)-1-phenyl-3-(trityloxy)propan-2-
yloxy)diphenylphosphine (10a). The following reagents were
combined in the amounts indicated according to the general
procedure for the phosphinite incorporation: 9a (100 mg, 0.18
mmol), DMAP (2.2 mg, 0.018 mmol), NEt3 (30 μL, 0.21
mmol), and chlorodiphenylphosphine (33 μL, 0.18 mmol).
The resulting slurry was loaded onto a plug of silica and
purified by flash chromatography (1 ꢀ 3 cm, 95% hexane,
5% ethyl acetate) to yield 10a as an oil (120 mg, 90% yield):
[R]26D -88.5 (c 0.39, CHCl3); IR (neat) 3054, 2901, 2847, 1738,
1490, 1448, 1434, 1350, 1299, 1217, 1155, 1071, 1029, 977, 924,
((1R,2S)-1-(Adamantylthio)-1-mesityl-3-methoxypropan-2-
yloxy)diphenylphosphine (7n). The following reagents were
combined in the amounts indicated according to the general
procedure for the phosphinite incorporation: 6n (26 mg, 0.07
mmol), DMAP (0.8 mg, 0.007 mmol), NEt3 (12 μL, 0.08
mmol), and chlorodiphenylphosphine (13 μL, 0.07 mmol).
The resulting slurry was loaded onto a plug of silica and
purified by flash chromatography (1 ꢀ 3 cm, 95% hexane, 5%
ethyl acetate) to yield 7n as an oil (33 mg, 85% yield): [R]26
D
-45.7 (c 0.42, CHCl3); IR (neat) 2903, 2848, 1479, 1450, 1434,
1376, 1343, 1300, 1254, 1126, 1093, 1053, 946, 909, 888, 737,
697 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.39-7.44 (m, 1H),
7.23-7.30 (m, 3H), 7.09-7.12 (m, 1H), 6.96-7 (m, 2H),
6.59-6.63 (m, 4H), 4.62 (d, 3J = 11.1 Hz, 1H), 4.33-4.40
(m, 1H), 3.86 (dxd, 2J = 10 Hz, 3J = 2.1 Hz, 1H), 3.80 (dxd,
2J = 10 Hz, 3J = 4.4 Hz, 1H), 3.14 (s, 3H), 2.38 (s, 3H), 2.37 (s,
3H), 2.2 (s, 3H), 1.98 (br s, 3H), 1.59-1.87 (m, 12H); 13C
NMR (100 MHz, CDCl3) δ 143.9 (d, J = 18 Hz), 142.3 (d, J =
13.9 Hz), 137.0, 136.6, 135.8, 135.3, 131.9, 130.0 (d, J = 22 Hz),
130.0 (d, J = 22 Hz), 128.9, 128.6, 128.1, 127.8 (d, J = 7 Hz),
127.4 (d, J = 6.6 Hz), 82.0 (d, J = 19.6 Hz), 73.5 (d, J = 2.7 Hz),
58.4, 43.7, 40.0 (d, J = 6.4 Hz), 36.2, 29.7, 21.8, 21.5 (d, J =
2.2 Hz), 20.8; 31P NMR (162, MHz, CDCl3) δ 117.8; HRMS
(ESþ) m/z calcd for C35H43O2NaPS 581.2619 [M þ Na]þ, found
581.2620.
898, 849, 742, 694 cm-1
;
1H NMR (400 MHz, CDCl3) δ
3
7.06-7.43 (m, 30H), 4.37-4.43 (m, 1H), 4.35 (d, J = 4.31
Hz, 1H), 3.20 (dxd, 2J = 9.8 Hz, 3J = 5.7 Hz, 1H), 2.96 (dxd,
2J = 9.8 Hz, 3J = 6.3 Hz, 1H), 1.93 (br s, 3H), 1.56-1.78 (br m,
12H); 13C NMR (100 MHz, CDCl3) δ 143.8, 143.0 (d, J =
19.8 Hz), 142.2 (d, J = 14.61 Hz), 141.1, 130.7 (d, J = 21.3 Hz),
130.5 (d, J = 22.0 Hz), 129.5, 128.9, 128.8, 128.6, 128.0 (d, J =
6.0 Hz), 127.9 (d, J = 6.0 Hz), 127.7, 127.7, 126.9, 126.4, 87.0,
84.4 (d, J = 19 Hz), 64.6 (d, J = 3.8 Hz), 46.9 (d, J = 5.7 Hz),
46.3, 43.7, 36.2, 29.7; 31P NMR (162, MHz, CDCl3) δ 117.7;
HRMS (ESþ) m/z calcd for C50H50O2PS 745.3269 [M þ H]þ,
found 745.3264.
((1R,2S)-1-(Cyclohexylthio)-1-mesityl-3-methoxypropan-2-
yloxy)diphenylphosphine (7l). The following reagents were com-
bined in the amounts indicated according to the general proce-
dure for the phosphinite incorporation: 6l (38 mg, 0.1 mmol),
DMAP (1.2 mg, 0.01 mmol), NEt3 (17 μL, 0.12 mmol), and
chlorodiphenylphosphine (19 μL, 0.1 mmol). The resulting slurry
was loaded onto a plug of silica and purified by flash chromato-
graphy (1 ꢀ 3 cm, 95% hexane, 5% ethyl acetate) to yield 7l as
an oil (41 mg, 79% yield): [R]27D -41.0 (c 0.36, CHCl3); IR (neat)
2924, 2851, 1738, 1435, 1375, 1217, 1094, 1052, 946, 738,
((1R,2S)-1-(tert-Butylthio)-1-mesityl-3-(trityloxy)propan-2-
yloxy)diphenylphosphine (10b). The following reagents were
combined in the amounts indicated according to the general
procedure for the phosphinite incorporation: 9b (79 mg, 0.15
mmol), DMAP (1.9 mg, 0.015 mmol), NEt3 (25 μL, 0.18
mmol), and chlorodiphenylphosphine (28 μL, 0.15 mmol).
The resulting slurry was loaded onto a plug of silica and
purified by flash chromatography (1 ꢀ 3 cm, 95% hexane,
5% ethyl acetate) to yield 10b as an oil (98 mg, 92% yield):
[R]26D þ13.1 (c 0.33, CHCl3); IR (neat) 3056, 2958, 2917, 1738,
1596, 1488, 1447, 1363, 1261, 1219, 1157, 1083, 1048, 1022,
1
697 cm-1; H NMR (400 MHz, CDCl3) δ 7.38-7.42 (m, 1H),
7.23-7.30 (m, 3H), 7.1-7.13 (m, 1H), 6.97-7.01 (m, 2H),
3
6.64-6.67 (m, 4H), 4.62 (d, J = 10.9 Hz, 1H), 4.48-4.54 (m,
1H), 3.82 (s, 1H), 3.81 (s, 1H), 3.18 (s, 3H), 2.57-2.64 (m, 1H),
2.38 (s, 3H), 2.29 (s, 3H), 2.20 (s, 3H), 2-2.04 (m, 1H), 1.86-1.91
(m, 1H), 1.66-1.78 (m, 2H), 1.52-1.58 (m, 1H), 1.17-1.37 (m,
6H); 13C NMR (100 MHz, CDCl3) δ 143.7, (d, J = 17.6 Hz),
142.2 (d, J = 14.7 Hz), 136.8, 136.5, 135.7, 134.9, 131.0, 130.0
(d, J = 21.6 Hz), 130.0 (d, J = 21.9 Hz), 128.9, 128.7, 128.2, 127.9
(d, J = 6.6 Hz), 127.4 (d, J = 7.1 Hz), 82.1 (d, J = 19.1 Hz), 73.7
1
998, 966, 943, 913, 807, 740, 694 cm-1; H NMR (400 MHz,
CDCl3) δ 7.03-7.30 (m, 21H), 6.9-6.94 (m, 2H), 6.72-6.75
(m, 2H), 6.45 (s, 1H), 6.38 (s, 1H), 4.4-4.47 (m, 1H), 4.21 (d,
3J = 11 Hz, 1H), 3.99 (dxd, 2J = 10 Hz, 3J = 1.5 Hz, 1H), 3.22
(dxd, 2J = 10 Hz, 3J = 6.5 Hz, 1H), 2.24 (s, 3H), 2.22 (s, 3H),
2.05 (s, 3H), 0.94 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 144.0,
2642 J. Org. Chem. Vol. 75, No. 8, 2010

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Caldentey and Pericas
JOCArticle
143.6 (d, J = 16 Hz), 142.4 (d, J = 16.8 Hz), 137.1, 135.7,
135.5, 135.4, 131.0, 130.4 (, d, J = 24 Hz), 129.7 (d, J = 21.67
Hz), 128.9, 128.9, 128.3, 127.8 (d, J = 6.6 Hz), 127.5, 127.3 (d,
J = 7.4 Hz), 126.7, 87.2, 82.9 (d, J = 20.4 Hz), 67.2 (d, J =
2.32 Hz), 44.1, 43.6 (d, J = 5.2 Hz), 31.2, 21.7 (d, J = 3.1 Hz),
20.7; 31P NMR (162, MHz, CDCl3) δ 116.8; HRMS (ESþ) m/z
calcd for C47H50O2PS 709.3269 [M þ Na]þ, found 709.3268.
((1R,2R)-1-(Adamantylthio)-1-phenyl-3-(trityloxy)propan-2-
yloxy)diphenylphosphine (10a-syn). The following reagents were
combined in the amounts indicated according to the general
procedure for the phosphinite incorporation: 9a-syn (100 mg,
0.18 mmol), DMAP (2.2 mg, 0.018 mmol), NEt3 (30 μL, 0.21
mmol), and chlorodiphenylphosphine (33 μL, 0.18 mmol). The
resulting slurry was loaded onto a plug of silica and purified by
flash chromatography (1 ꢀ 3 cm, 95% hexane, 5% ethyl acetate)
CDCl3) δ 147.3 (d, J = 26.6 Hz), 147.3 (d, J = 27 Hz), 143.4,
136.7, 134.5 (d, J = 13 Hz), 133.1, 133.2, 129.9, 129.6, 129.2 (d,
J = 12.2 Hz), 128.8 (d, J = 17.8 Hz), 128.7, 128.6, 128.5, 128.2,
127.6, 87.1, 80.6, 62.9 (d, J = 6.8 Hz), 60.6, 47.6 (d, J = 5.2 Hz),
44.3, 42.7, 35.8, 30.8; 31P NMR (162 MHz, CD2Cl2) δ 110.8.
X-ray quality crystals were grown by slow vapor diffusion of
Et2O into a solution of PdCl2-10a-syn in CH2Cl2 to yield ortho-
rhombic crystals. A suitable crystal (0.15 ꢀ 0.15 ꢀ 0.06 mm) was
chosen for X-ray diffraction analysis; see the Supporting Infor-
mation.
General Procedure for the Palladium-Catalyzed Allylic Alky-
lation Reaction. To a Schlenck flask containing ligand 10b-syn
(4.215 mg, 0.006 mmol) and [(C3H5)PdCl]2 (1.088 mg, 0.006
mmol Pd) was added CH2Cl2 (0.6 mL). After 1 h of stirring at rt,
1,3-diphenylpropenyl acetate (60 mg, 0.238 mmol) dissolved in
CH2Cl2 (0.6 mL) was added, followed by dimethyl malonate
(82 μL, 0.71 mmol), N,O-bis(trimethylsilyl)acetamide (BSA)
(177 μL, 0.71 mmol), and a pinch of KOAc. The mixture was
stirred at room temperature for 20 min and then was diluted
with diethyl ether and washed with saturated NH4Cl(aq). The
organic layers were dried over MgSO4 and filtered, and the
solvents were evaporated in vacuo. The residue was purified by
flash chromatrography (85% hexane, 15% EtOAc) to afford
(S,E)-dimethyl 2-(1,3-diphenylallyl)malonate as a colorless oil.
The absolute configuration of the product was assigned by
comparing the sign of its specific rotation with literature data.5j
HPLC analysis (Chiralcel-AD-H, hexane/2-propanol 95:5,
1 mL/min, 254 nm, tR = 21 min, tS = 24 min) showed the ee
to be 96%.
(S)-Methyl 2-Carbomethoxy-3,5,5-triphenylpent-4-enoate (P2).
The following reagents were combined in the amounts indicated
according to the general procedure for the allylic alkylation with
dimethyl malonate: 9a-syn (2.48 mg, 0.003 mmol), [(C3H5)PdCl]2
(0.54 mg, 0.003 mmol), 1,3,3-triphenylpropenyl acetate (S2)
(39 mg, 0.12 mmol), dimethyl malonate (41 μL, 0.36 mmol),
BSA (88 μL, 0.36 mmol), and a pinch of potassium acetate. The
product was purified by flash chromatography (9:1 hexane/ethyl
acetate) to yield P3 as an oil (26 mg, 54% yield). The absolute
configuration of the product was assigned by comparing the sign
of its specific rotation with literature data. [R]25D = -182 (c 0.3,
CH2Cl2); [R]25D = -186 (c 0.44, CH2Cl2) for optically pure P2.
HPLC analysis (AD-H column, 0.3 mL/min n-hexane/2-propanol
97:3: tR = 44.7 min, tS = 46.7 min) showed the ee to be 97%.
(S)-Methyl 2-Carbomethoxy-3-methyl-5,5-diphenylpent-4-
enoate (P3). The following reagents were combined in the
amounts indicated according to the general procedure for the
allylic alkylation with dimethyl malonate: 9a (5.3 mg, 0.007
mmol), [(C3H5)PdCl]2 (1.08 mg, 0.006 mmol), 4,4-diphenylbute-
nyl-2-acetate (S3) (63 mg, 0.24 mmol), dimethyl malonate (82 μL,
0.71 mmol), BSA (177 μL, 0.71 mmol), and a pinch of potassium
acetate. The product was purified by flash chromatography (9:1
hexane/ethyl acetate) to yield P3 as an oil (33 mg, 40% yield).
HPLC analysis (OD-H column, 1 mL/min n-hexane/2-propanol
99:1: tR = 9.1 min, tS = 10.6 min) showed the ee to be 82%.
General Procedure for the Palladium-Catalyzed Allylic Ami-
nation Reaction. To a Schlenk flask containing ligand 10b-syn
(4.215 mg, 0.006 mmol) and [(C3H5)PdCl]2 (0.725 mg, 0.004
mmol Pd) was added CH2Cl2 (0.5 mL). After 1 h of stirring at rt,
1,3-diphenylpropenyl acetate (40 mg, 0.16 mmol) dissolved in
CH2Cl2 (0.5 mL) was added, followed by benzylamine (52 μL,
0.476 mmol). The mixture was stirred at room temperature for
4 h. Then the mixture was diluted with diethyl ether and washed
with saturated NH4Claq. The organic layers were dried over
MgSO4 and filtered and the solvents were evaporated in vacuo.
The residue was purified by flash chromatrography (87%
hexane, 13% EtOAc) to afford (R,E)-N-benzyl-1,3-diphenyl-
prop-2-en-1-amine (97% yield) as a colorless oil. The absolute
configuration of the product was assigned by comparing the sign
to yield 10a-syn as a white solid (120 mg, 90% yield): [R]27
D
-73.1 (c 0.51, CHCl3); IR (neat) 3054, 2901, 1597, 1490, 1447,
1434, 1342, 1071, 741, 694 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.37-7.41 (m, 4H), 7.32-7.35 (m, 6H), 7.27-7.29 (m, 3H),
7.18-7.24 (m, 14H), 7.08-7.1 (m, 3H), 4.22-4.28 (m, 1H), 3.36
(dxd, 2J = 9.5 Hz, 3J = 5.4 Hz, 1H), 3.16 (dxd, 2J = 10.4 Hz,
3J = 5.4 Hz, 1H), 1.88 (br s, 3H), 1.51-1.69 (br m, 12H); 13
C
NMR (100 MHz, CDCl3) δ 143.9, 142.8 (d, J = 19.2 Hz), 142.9,
142.2 (d, J = 15.9 Hz), 131.0 (d, J = 22.7 Hz), 130.5 (d, J =
22.2 Hz), 129.0, 128.9, 128.8, 128.7, 128.0 (d, J = 7.3 Hz), 128.0
(d, J = 7.3 Hz), 127.8, 127.7, 126.8, 126.5, 86.1, 84.6 (d, J =
18.3 Hz), 65.3 (d, J = 4.3 Hz), 47.6 (d, J = 5.2 Hz), 45.7, 43.7,
36.2, 29.7; 31P NMR (162 MHz, CDCl3) δ 117.2; HRMS (ESþ)
m/z calcd for C50H49O2PSNa 767.3089 [M], found 767.3052.
((1R,2R)-1-(tert-Butylthio)-1-phenyl-3-(trityloxy)propan-2-
yloxy)diphenylphosphine (10b-syn). The followingreagents were
combined in the amounts indicated according to the general
procedure for the phosphinite incorporation: 9b-syn (100 mg,
0.19 mmol), DMAP (2.4 mg, 0.019 mmol), NEt3 (32 μL, 0.23
mmol), and chlorodiphenylphosphine (35 μL, 0.19 mmol). The
resulting slurry was loaded onto a plug of silica and purified by
flash chromatography (1 ꢀ 3 cm, 95% hexane, 5% ethyl acetate)
to yield 10b-syn as a white solid (112 mg, 83% yield): [R]27D -52.5
(c 0.51, CHCl3); IR (neat) 3057, 2959, 2914, 2860, 1597, 1448,
1260, 1064, 984, 926, 799, 739, 693 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.53-7.63 (m, 4H), 7.07-7.32 (m, 21H), 6.62 (s, 1H),
3
6.57 (s, 1H), 4.54-4.62 (m, 1H), 4.24 (d, J = 8.9 Hz, 1H),
2.96-3.05 (m, 2H), 2.33 (s, 3H), 2.17 (s, 3H), 2.15 (s, 3H), 0.95
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 143.7, 143.1 (d, J =
17.6 Hz), 142.7 (d, J = 16.1 Hz), 137.2, 135.8, 135.5, 134.2, 132.1
(d, J = 22.7 Hz), 131.4, 130.4 (d, J = 22.3 Hz), 129.0, 128.9,
128.6, 127.9 (d, J = 6.9 Hz), 127.7 (d, J = 7.3 Hz), 127.4, 126.6,
87.1, 84.0 (d, J = 19.7 Hz), 66.4 (d, J = 2.9 Hz), 46.8 (d, J =
4.4 Hz), 43.83, 31.1, 22.2, 21.5, 20.7; 31P NMR (162, MHz,
CDCl3) δ 118.6; HRMS (ESþ) m/z calcd for C47H50O2PS
709.3269 [M - H]-, found 709.3250.
((1R,2R)-1-(Adamantylthio)-1-phenyl-3-(trityloxy)propan-2-
yloxy)diphenylphosphinepalladium(II) Chloride (10a-syn) PdCl2.
3
To a Schlenk flask containing the thiophosphinite ligand
10a-syn (34.3 mg, 0.046 mmol) in CH2Cl2 (1 mL) was added
(MeCN)2PdCl2 (11.9 mg 0.046 mmol), and the reaction was
stirred for 40 min. The solution was concentrated in vacuo,
and the residue was diluted with CH2Cl2 (0.6) mL. Then Et2O
(10 mL) was added rapidly with stirring to precipitate PdCl2-
10a-syn, which was filtered and dried in vacuo overnight (42 mg,
99% yield): mp >200 °C; [R]27 -108.2 (c 0.54, CH2Cl2); IR
D
(neat) 3054, 2901, 1597, 1490, 1447, 1434, 1342, 1071, 741,
694 cm-1; 1H NMR (400 MHz, CD2Cl2) δ 8.28-8.33 (m, 2H),
7.81-7.86 (m, 2H), 7.60-7.65 (m, 1H), 7.52-7. 57 (m, 2H),
7.40-7.43 (m, 1H), 7.08-7.33 (m, 22H), 4.41 (d, J3 = 10.6 Hz,
1H), 3.82-3.88 (m, 1H), 2.85 (dxd, 2J = 10.6 Hz, 3J = 2.2 Hz,
1H), 2.39 (dxd, 2J = 10.6 Hz, 3J = 2.2 Hz, 1H), 2.22 (br d, 3H),
1.99 (br s, 6H), 1.55-1.64 (br m, 6H); 13C NMR (100 MHz,
J. Org. Chem. Vol. 75, No. 8, 2010 2643

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Caldentey and Pericas
JOCArticle
of its specific rotation with literature data.5j HPLC analysis
(Chiralcel-OJ, hexane/2-propanol 87:13, 0.5 mL/min, 254 nm,
tS = 14.2 min, tR = 17.5 min) showed the ee to be 94%.
General Procedure for the Palladium-Catalyzed Allylic Etheri-
fication Reaction. To a Schlenk flask containing ligand 10b-syn
(3.717 mg, 0.005 mmol) and [(C3H5)PdCl]2 (0.914 mg, 0.005
mmol Pd) was added toluene (0.6 mL). After 1 h of stirring at rt,
1,3-diphenylpropenyl acetate (31.5 mg, 0.125 mmol) dissolved
in CH2Cl2 (0.5 mL) was added, followed by cesium carbonate
(122 mg, 0.375 mmol) and benzyl alcohol (39 μL, 0.375 mmol).
The mixture was stirred at 0 °C for 3 h, and then the mixture was
product was assigned by comparing the sign of its specific
rotation with literature data.5t HPLC analysis (Chiralcel-
OJ-H, hexane/2-propanol 98:2, 0.75 mL/min, 254 nm, tS
27.9 min, tR = 34 min) showed the ee to be 94%.
=
Acknowledgment. This work was funded by MICINN
(Grant No. CTQ2008-00947/BQU), DIUE (Grant No.
2009SGR623), Consolider Ingenio 2010 (Grant No.
CSD2006-0003), and the ICIQ Foundation. X.C. thanks
MICINN for a FPU fellowship.
diluted with ethyl acetate and washed with saturated NH4Claq
.
1
The organic layers were dried over MgSO4 and filtered, and the
solvents were evaporated under vacuum. The residue was
purified by flash chromatography (95% hexane, 5% Et2O) to
afford (R,E)-(3-(benzyloxy)prop-1-ene-1,3-diyl)dibenzene (96%
yield) as a colorless oil. The absolute configuration of the
Supporting Information Available: Copies of H and 13C
NMR spectra. Crystallographic data for (10a-syn) PdCl2 and
3
4 m PdCl2 (CIF). Cartesian coordinates and energies of TS C2
3
and TS C3 calculated at the BLYP/6-31G (d) level. This material
is available free of charge via the Internet at http://pubs.acs.org.
2644 J. Org. Chem. Vol. 75, No. 8, 2010