Practical asymmetric catalytic synthesis of spiroketals and chiral diphosphine ligands

Article abstract of DOI:10.1002/adsc.201300380

A practical procedure has been developed for efficient synthesis of chiral aromatic spiroketals and the relevant diphosphine ligands. The procedure includes first asymmetric hydrogenation of readily available α, α'-bis(2-benzyloxyarylidene) ketones cat-al

Full text of DOI:10.1002/adsc.201300380

FULL PAPERS
DOI: 10.1002/adsc.201300380
Practical Asymmetric Catalytic Synthesis of Spiroketals and
Chiral Diphosphine Ligands
Xubin Wang,a Peihua Guo,a Xiaoming Wang,a,* Zheng Wang,a and Kuiling Dinga,*
a
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, Peopleꢀs Republic of China
E-mail: xiaoming@sioc.ac.cn or kding@mail.sioc.ac.cn
Received: May 2, 2013; Revised: July 16, 2013; Published online: September 10, 2013
This article is dedicated to Professor Irina Petrovna Beletskaya for her contribution to metal-catalyzed reac-
tions.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300380.
Abstract: A practical procedure has been developed high yields (77–94%) with good diastereoselectivities
for efficient synthesis of chiral aromatic spiroketals (trans/cis=81/19 to 96/4), and excellent enantioselec-
and the relevant diphosphine ligands. The procedure tivities for the trans products (97–>99% ee). In addi-
includes first asymmetric hydrogenation of readily tion, the reaction of aromatic spiroketal difluoride
available a,a’-bis(2-benzyloxyarylidene) ketones cat- (R,R,R)-4b with potassiodiarylphosphide (KPAr2) in
alyzed by the Ir(I)/SpinPHOX (S,S)-1a (0.5–1 mol%) refluxing tertahydrofuran (THF) has also provided
and subsequent hydrogenative deprotection of the an alternative and practical synthesis of chiral spiro-
resultant benzyl ethers catalyzed by palladium on ketal-based diphosphine (SKP) ligands in 78–95%
carbon (Pd/C), as well as simultaneous spiroketaliza- yields on multigram scale.
tion of the corresponding diphenolic ketones by
(S,S)-1a in one pot. The corresponding chiral aro- Keywords: asymmetric catalysis; diphosphine li-
matic spiroketals (R,R,R)-4a–j have been obtained in gands; hydrogenation; iridium; spiroketals
Introduction
diazooxindoles.[3j] List and co-worker independently
reported an elegant example of spiroacetal synthesis
The aromatic spiroketals have attracted considerable via a catalytic asymmetric spiroketalization of various
attention because of their unique structural motifs oc- hydroxyl enol ethers using structurally confined chiral
curring in many bioactive natural products,[1] pharma- imidodiphosphoric acids as the catalysts.[11] A similar
ceuticals,[2] and ligands in transition metal-catalyzed procedure using BINOL-derived chiral phosphoric
reactions.[3] Despite the fact that numerous ap- acids as the catalysts for the stereoselective acetaliza-
proaches have been developed for the synthesis of tion various achiral and chiral cyclic enol ethers have
various spiroketals,[4–8] the direct catalytic enantiose- also been reported by Nagorny and co-workers.[12]
lective synthesis of chiral spiroketals is only a recent Very recently, Gong et al. developed a gold(I)/chiral
event and documented examples are still rather limit- phosphoric acid relay catalysis for highly efficient
ed so far.[9–13] We have recently developed the first
catalytic enantioselective synthesis of aromatic spiro-
ketals by a tandem hydrogenation and spiroketaliza-
tion of a,a’-bis(2-hydroxyarylidene) ketones using
Ir(I)/SpinPHOX 1[14] (Figure 1) as the catalyst.[10] This
methodology led to the development of a type of spi-
roketal-based diphosphine ligand (SKPs),[15] which
demonstrated excellent performance in Pd-catalyzed
asymmetric allylic amination of a variety of racemic
Morita–Baylis–Hillman adducts[3f] and Au(I)-cata-
lyzed stereoselective cyclopropanation of olefins with Figure 1. Ir(I)/SpinPHOX catalysts (S,S)- and (R,S)-1a–d.
2900
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 2900 – 2907

Practical Asymmetric Catalytic Synthesis of Spiroketals and Chiral Diphosphine Ligands
access to aromatic spiroacetals from a three-compo- Results and Discussion
nent reaction of salicylaldehydes, anilines, and alkyn-
A
We have previously examined the reaction of a,a’-
Although our previously reported catalytic system bis(2-methoxyarylidene) ketone, a substrate protected
has provided an efficient synthesis of a variety of opti- by the methyl group, using the afore-mentioned strat-
cally active aromatic spiroketals,[10] the methodology egy.[10] Although the hydrogenation catalyzed by
still suffers from some limitations. Specifically, the (S,S)-1a proceeded smoothly to give the correspond-
a,a’-bis(2-hydroxyarylidene)
substrates
bearing ing product in 90% yield with a diastereomeric ratio
strongly electron-donating substituents on the phenyl (dr=trans/cis) of 92:8 and 99% ee for the trans
rings were found to be difficult to prepare via the isomer, the subsequent demethylation–spiroketaliza-
direct aldol condensation of the corresponding salicy- tion using BBr3 proved to be not successful, resulting
laldehydes and cyclohexanone, thus limiting the bis(2- in only a modest yield (10%) of trans spiroketal prod-
hydroxyarylidene) substrate scope in the reaction. uct with a low ee value (15%).[10] Accordingly, we
Moreover, the catalyst loadings employed in the hy- moved to test the viability of using TBS-protected
drogenation–spiroketalization were usually high (1– substrate S2 in the synthesis (for details, see the Sup-
5 mol%) for certain substrates. Herein, we wish to porting Information). In this case, the hydrogenation
report an improved method for the catalytic enantio- of S2 proceeded smoothly as well, to afford the corre-
selective synthesis of aromatic spiroketals with special sponding hydrogenation product S3 in high yield
attention on the efficient access to the aromatic spiro- (94%) with excellent diastereoselectivity (trans/cis=
ketals with electron-donating substituents. Meanwhile, 18/1) and nearly perfect chiral induction (>99% ee).
an alternative and practical approach for the synthesis Unfortunately, subsequent attempts to desilylate S3
of chiral spiroketal-based diphosphine ligands (SKPs) with HF·pyridine, Et3N·3HF, BF3·OEt2, or TBAF led
on the multigram scale has also been developed.
to an intractable mixture in each case, from which
With regards to the limitations in our previous pro- neither the desilylated product nor the targeted acetal
tocol, we speculated that both the free phenolic OH 4a could be isolated (see the Supporting Informa-
groups and the electron-donating groups in the salicy- tion).
laldehydes might negatively influence their aldol reac-
Gratifyingly, the results obtained with benzyl-pro-
tivity towards the ketone substrates. Furthermore, the tected bis(2-hydroxyarylidene) 2a proved to be prom-
purification of resultant a,a’-bis(2-hydroxyarylidene) ising as shown by the results summarized in Table 1.
substrates seems also a challenging issue because of As expected, the hydrogenation of 2a in the presence
their strong polarities and poor crystalline properties. of (S,S)-1a afforded 3a in excellent yield (97%) with
In this context, we envisioned that modification of the high diastereoselectivity (trans/cis=91/9) and excel-
OH sites with suitable protecting groups[16] might cir- lent ee (>99%). Subsequent Pd/C-catalyzed hydroge-
cumvent the problems. Such a protecting group (PG) native deprotection of isolated 3a resulted in only the
should allow for their ready synthesis and separation, partial formation of the spiroketal product (R,R,R)-4a
high diastereo- and enantioselective hydrogenation in 39% yield and nearly enantiopure trans-isomer, to-
(from 2 to 3), as well as facile deprotection and subse- gether with an unidentifiable mixture that may be
quent spiroketalization to the corresponding enan- composed of the bisphenolic product, hemiketals, and
tioenriched aromatic spiroketals 4 (Scheme 1).
some tautomers formed thereof. Obviously, the pres-
ence of Pd/C catalyst alone was not effective enough
for the clean transformation of the debenzylation
product to 4a. It is well-known that Lewis or Brønsted
acids can significantly promote the cyclization of
chiral dihydroxy ketones and analogues to spiroke-
tals.[4] Accordingly, several acids including Brønsted
acid TsOH·H2O or Lewis acidic IrCl3·3H2O or
BF3·OEt2 were tested by addition into the unknown
mixture mentioned above. Indeed, the use of the
acids resulted in a complete transformation of the
mixture to the target spiroketal (R,R,R)-4a, although
HOAc was found to be less effective for the reaction
even after a prolonged reaction time (24 h, entry 4).
While both TsOH·H2O and IrCl3·3H2O led to
(R,R,R)-4a with a high dr ratio (93/7 and 95/5, respec-
tively) and >99% ee for the trans-isomer (entries 1
and 2), the dr value using BF3·OEt2 declined dramati-
Scheme 1. Proposed synthesis of spiroketals (4) via asym-
metric hydrogenation of protected bis(2-hydroxyarylidenes
(2) followed by deprotection–spiroketalization of 3. PG=
protecting group.
cally to 44:56 (entry 3), presumably caused by BACHTUNGTRENNUNG(III)-
Adv. Synth. Catal. 2013, 355, 2900 – 2907
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2901

Xubin Wang et al.
FULL PAPERS
Table 1. Asymmetric hydrogenation of 2a and hydrogenative debenzylation and spiroketalization of 3a.
Entry
Acid
Time t [h]
Conversion[a] [%]
dr[b]
ee[c] [%]
1
2
3
4
TsOH·H2O
IrCl3·3H2O
BF3·OEt2
HOAc
1
10
1
> 99
> 99
> 99
0
93:7
95:5
44:56
–
>99
>99
97
24
–
[a]
1
Determined by H NMR.
[b]
[c]
1
dr=trans/cis, determined by H NMR.
Determined by chiral HPLC for trans-4a.
induced enolization–isomerization of the ketonic sub- roketalization of the dihydroxy ketone generated
strates during the cyclization. TsOH·H2O turned out from the subsequent Pd/C-catalyzed hydrogenative
to be optimal for this transformation, leading to the debenzylation step. Thus, the reaction mixture from
clean transformation to spiroketal (R,R,R)-4a with ex- the (S,S)-1a-catalyzed hydrogenation of 2a, without
cellent dr and >99% ee in 1 h.
isolation of the intermediate product 3a and removal
In our previous work on the catalytic enantioselec- of catalyst (S,S)-1a, was directly submitted to the Pd/
tive synthesis of aromatic spiroketals,[10] the Ir com- C-catalyzed hydrogenative debenzylation and spiroke-
plexes were found to play a dual role in the reaction, talization. In this case, the corresponding spiroketal
i.e., to catalyze the asymmetric hydrogenation of a,a’- was obtained in 88% isolated yield with 89:11 dr and
bis(2-hydroxyarylidene)s and to promote the spiroke- >99% ee, indicating that such a one-pot procedure
talization of the resulting hydrogenated bisphenolic can provide an efficient access to enantioenriched spi-
ketones as well. The spiroketalization was proposed roketals (Scheme 2).
to be induced either by the high-valent Lewis acidic
Encouraged by these preliminary results, we
switched to screen the chiral Ir(I)/SpinPHOX cata-
[18]
Ir species[17] or by the acidic Ir H intermediates
À
generated in the reaction systems. For the reaction of lysts (S,S)- and (R,S)-1a–d (Figure 1) for the asym-
benzyl-protected bis(2-hydroxyarylidene) 2a, we fur- metric hydrogenation of 2a. The reactions were con-
ther explored the possibility to effect the second use ducted in dichloromethane for 6 h under a hydrogen
of the Ir complex (S,S)-1a for the acceleration of spi- pressure of 50 atm, and the results are shown in
Scheme 2. One-pot procedure for the synthesis of (R,R,R)-4a.
2902
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 2900 – 2907

Practical Asymmetric Catalytic Synthesis of Spiroketals and Chiral Diphosphine Ligands
Table 2. Catalyst screening for the asymmetric hydrogenation of a,a’-bis(2-benzyloxyarylidene) ketone 2a.[a]
Entry
Catalyst (X mol%)
Conversion[b] [%]
dr[c]
Yield[d] [%]
ee[e] [%]
1
2
3
4
5
6
7
8
N
>99
69
>99
77
>99
>99
>99
16
>99
>99
20
91:9
87
51
44
62
81
80
67
15
87
84
18
>99 (À)
>99 (+)
>99 (À)
>99 (+)
>99 (À)
>99 (+)
98 (À)
83:17
56:44
84:16
82:18
90:10
68:31
ND
91:9
90:10
ND
ND
9
10
11
>99 (À)
>99 (À)
ND
[a]
Reaction conditions: P(H2)=50 atm, 2a (0.1 mmol), Ir(I) catalyst (0.1–1 mol%), CH2Cl2 (2 mL), room temperature, 6 h.
[b]
[c]
[d]
[e]
1
Determined by H NMR.
dr=trans/cis, determined by H NMR.
1
Yield of isolated trans-3a.
The ee value of the trans-3a was determined by chiral HPLC.
Table 2. Excellent ee values (98–>99%) were ob- asymmetric hydrogenation catalyzed by (S,S)-1a, sub-
tained for the trans-3a in most cases, with the sense of sequently to hydrogenative debenzylation of the re-
the asymmetric induction being dictated by the chiral- sultant benzyl ethers catalyzed by Pd/C, and simulta-
ity of the spiro backbone of the SpinPHOX ligands neously to spiroketalization of the diphenolic ketones
(entries 1–8). On the other hand, the catalytic activity by (S,S)-1a again in the presence of H2, leading to the
and the diastereoselectivity (dr) varied dramatically formation of the corresponding chiral aromatic spiro-
with the change of the substituents at the oxazoline ketals (R,R,R)-4b–j in high overall yields (77–94%)
fragments of the ligands. In terms of both the catalytic with good diastereoselectivities (trans/cis=81/19 to
efficiency and the diastereoselectivity, (S,S)-1a proved 96/4), and excellent enantioselectivities for the trans
to be the optimal catalyst, affording (À)-trans-3a in products (97–>99% ee). It is noteworthy that aromat-
87% yield with a dr of 91:9 and >99% ee (entry 1). ic spiroketals with strongly electron-donating groups
By contrast, (R,S)-1c was found to be optimal for the (OH, OMe, or OEt) on the phenyl rings are readily
production of (+)-trans-3a, a yield of 81% with 90:10 accessible using this protocol (entries 3–6), while the
dr and >99% ee being obtained in this case (entry 6). aromatic spiroketals (R,R,R)-4e with free phenolic
Under the otherwise identical conditions, the catalyst hydroxy functionality may find utility as chiral ligand
loading of (S,S)-1a can be decreased from 1.0 to 0.5 or organocatalyst for asymmetric synthesis.[19] Mean-
or 0.2 mol%, respectively, without significant deterio- while, as shown in entry 9, the transformation of the
ration in substrate conversions or product dr and ee substrate with different substituents on each phenyl
values (entries 9 and 10 vs. 1). Further lowering the ring also proceeds smoothly to the corresponding
catalyst loading to 0.1 mol%, however, led to a dra- product (R,R,R)-4j with good yield, high dr and excel-
matic decline of the conversion to 20% (entry 11).
With the optimized catalysts in hands, we proceed-
lent ee.
Encouraged by the results obtained above, we fur-
ed to extend the one-pot procedure (Scheme 2) to the ther extended the methodology to a large-scale syn-
synthesis of other aromatic spiroketals. The benzyl- thesis of the spiroketal-based diphosphine ligands
protected bis(2-hydroxyarylidenes) 2b–j were readily (SKPs),[3f] to demonstrate the practical synthetic utili-
obtained in good yields from the aldol condensation ty of the one-pot catalytic approach. As shown in
of the corresponding benzylated salicylaldehydes with Scheme 3, the key synthetic intermediate (R,R,R)-4b
cyclohexanone, and were easily purified by simple re- was prepared by following the protocol with a slight
crystallization. Substrates 2b–j proved to be well ame- modification. Benzylation of 3-fluoro-2-hydroxyben-
nable to the one-pot procedure for the synthesis of zaldehyde (5, 100 g) followed by aldol condensation
spiroketals. As shown in Table 3, a,a’-bis(2-benzyl- with cyclohexanone in one pot, afforded 151 g of
ACHTUNGTRENNUNGoxyarylidene) ketones 2b–j were first submitted to (2E,6E)-2,6-bis(2-(benzyloxy)-3-fluorobenzylidene)cy-
Adv. Synth. Catal. 2013, 355, 2900 – 2907
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2903

Xubin Wang et al.
FULL PAPERS
clohexanone (2b) in total 81% yield. Compound 2b aromatic spiroketal difluoride (R,R,R)-4b was easily
was readily purified by recrystallization from 90% converted into the spiroketal-based diphosphine li-
aqueous ethanol, thus obviating the need for cumber- gands (R,R,R)-6a–c in good yields (78–95%) in up to
some column chromatography. For the transformation tens of grams scales, by reaction with either KPPh2 or
of large quantities of 2b to (R,R,R)-4b, a catalytic KH and HPAr2 in refluxing THF (Scheme 3).[20] In
amount of TsOH was used along with Pd/C to facili- comparison with the previous approach for the syn-
tate the spiroketalization of the debenzylated product. thesis of SKP ligands, this method is obviously more
By using this procedure, 50 g of 2b was smoothly convenient with higher total yields, and is particularly
transformed to 24.8 g of (R,R,R)-4b (79% overall amenable to the practical synthesis of these com-
yield) with excellent enantiopurity (>99% ee). The pounds in large scales.
Table 3. Synthesis of various chiral aromatic spiroketals via a one-pot procedure.[a]
Entry
1
Product
dr[b]
Yield [%][c]
ee [%][d]
>99
96:4
93
2
3
88:12
81:19
77
80
>99
>99
4[e]
92:8
80
78
>99
>99
5
81:19
6
92:8
90
94
>99
>99
7
96:4
2904
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 2900 – 2907

Practical Asymmetric Catalytic Synthesis of Spiroketals and Chiral Diphosphine Ligands
Table 3. (Continued)
Entry
Product
dr[b]
Yield [%][c]
85
ee [%][d]
8
88:12
97
9
89:11
86
98
[a]
Reaction conditions: substrate 2a–j (0.3 mmol), P(H2)=50 atm, (S,S)-1a (0.5–1.0 mol%), CH2Cl2 (5 mL), room tempera-
ture, 6 h. The resulting mixture, after release of H2, was submitted to debenzylation and spiroketalization by charging
with 5% Pd (10–30% wt/wt), P(H2)=20 atm, room temperature, 24 h.
dr=trans/cis, determined by H NMR.
Yield of isolated trans product.
The ee value of the trans isomer was determined by chiral HPLC.
1 mol% of (S,S)-1a was used.
[b]
[c]
[d]
[e]
1
Scheme 3. Practical asymmetric synthesis of the spiroketal compound (R,R,R)-4b and chiral SKP ligands (R,R,R)-6a–c: a)
BnBr, K2CO3, DMF; then cyclohexanone, aqueous NaOH; b) (S,S)-1a (0.2 mol%), H2 (65 atm), CH2Cl2, room temperature,
20 h; then Pd/C, H2 (20 atm), room temperature, 24 h; then TsOH·H2O (0.1 equiv,), room temperature, 1 h. c) Method A for
(R,R,R)-6a synthesis: KPPh2 in refluxing THF, 6 h. Method B for 6b–c synthesis: HPAr2, KH, in refluxing THF, 6 h.
Conclusions
a straightforward and convenient route to the prepa-
ration of the chiral spiroketals. Remarkably, the reac-
In summary, an improved procedure has been devel- tion of aromatic spiroketal difluoride (R,R,R)-4b with
oped for the efficient synthesis of chiral aromatic spi- KPAr2 in refluxing THF has also provided an alterna-
roketals and the relevant diphosphine ligands. The tive and facile synthesis of chiral SKP ligands in 78–
procedure includes first asymmetric hydrogenation of 95% yields in up to tens of grams scales. This synthet-
readily available a,a’-bis(2-benzyloxyarylidene) ke- ic advance will definitely stimulate future researches
tones catalyzed by (S,S)-1a (0.5–1 mol%) and subse- on the applications of this type of molecular platform
quent hydrogenative deprotection of the resultant from both academic and industrial communities.
benzyl ethers catalyzed by Pd/C, as well as simultane-
ous spiroketalization of the corresponding diphenolic
ketones by (S,S)-1a in one pot. The corresponding
Experimental Section
chiral aromatic spiroketals (R,R,R)-4a–j has been ob-
tained in high yields (77–94%) with good diastereose-
lectivities (trans/cis=81/19 to 96/4), and excellent
enantioselectivities for the trans products (97–>99%
One-Pot Procedure for the Synthesis of Chiral
Aromatic Spiroketals (R,R,R)-4a–j, General
Procedure
ee). The ease of preparation of the substrates com-
bined with the lower catalytic loading has provided (S,S)-1a catalyst (0.5–1 mol%) and a magnetic stirring bar
To a glass tube containing the substrate 2 (0.3 mmol), Ir(I)-
Adv. Synth. Catal. 2013, 355, 2900 – 2907
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2905

Xubin Wang et al.
FULL PAPERS
was added anhydrous CH2Cl2 (5 mL) under an argon atmos-
phere. The tube was transferred into a Parr autoclave in
a glovebox, the autoclave was then purged three times with
hydrogen and finally pressurized to 50 atm. The reaction
mixture was stirred at room temperature for 6 h. After care-
fully releasing H2 into a hood, an amount of 5% Pd/C (10–
30% wt/wt relative to 2) was added slowly into the reaction
mixture, and the autoclave was again purged three times
with H2 and finally pressurized to 20 atm. The reaction mix-
ture was stirred at room temperature for 24 h, and then the
hydrogen gas was released in a hood. The conversion of sub-
strates and dr values of the products were determined by
1H NMR analysis of an aliquot of the crude mixture. After
removal of the solvent under vacuum, the residue was puri-
fied by column chromatography on silica gel with hexane/
ethyl acetate as the eluent to afford the spiroketal products
(R,R,R)-4a–i. The ee values of the spiroketals were deter-
mined by chiral HPLC.
The mixture was heated at reflux for 6 h and then cooled
down to room temperature, followed by addition of water
(200 mL). The resulting mixture was extracted with CH2Cl2
(3ꢂ150 mL). The combined organic layers were dried over
sodium sulfate. After removal of sodium sulfate solids by fil-
tration, the filtrate was concentrated under vacuum. Purifi-
cation of the residue by flash chromatography [SiO2: ethyl
acetate/petroleum ether (1:50, v/v)] afforded the diphos-
phine product (R,R,R)-6a as a white solid; yield: 22.9 g
(95%); >99% ee by chiral HPLC).
Acknowledgements
We thank the financial support of this work from the Major
Basic Research Development Program of China (grant no.
2010CB833300), the National Natural Science Foundation of
China (grant nos. 21121062, 21172237, 21232009), the Chi-
nese Academy of Sciences, and the Science and Technology
Commission of Shanghai Municipality.
Procedure for Catalytic Asymmetric Synthesis of
(R,R,R)-4b on a Large Scale
Benzyl bromide (102.4 mL, 0.85 mol) was added dropwise to
a solution of 3-fluoro-2-hydroxybenzaldehyde (5) (100 g,
0.71 mol) and anhydrous K2CO3 (197 g, 1.4274 mol) in DMF
(200 mL) at room temperature. After the reaction mixture
had been stirred for 2 h, TLC detection indicated the com-
pletion of the reaction. To the stirred reaction mixture was
added aqueous NaOH (20 wt%, 228 mL, 1.42 mol), followed
by the dropwise addition of cyclohexanone (35.5 mL,
0.34 mol). The resulting mixture was stirred at room temper-
ature for 19 h, followed by addition of H2O (300 mL) to
afford a yellow precipitate which was filtered off, washed
with distilled H2O, and dried under vacuum. The crude
product was purified by recrystallization from the 90%
aqueous ethanol to afford 2b as yellow crystalline solid;
yield: 151 g (81%).
Under an argon atmosphere, CH2Cl2 (130 mL) was added
into a 250-mL vial containing 2b (50 g, 0.095 mol), Ir(I)-
(S,S)-1a catalyst (315 mg, 0.2 mol%) and the magnetic stir-
ring bar. The vial was then transferred into a Parr autoclave
in a glovebox, which was purged three times with hydrogen
and finally pressurized to 65 atm. The resulting mixture was
stirred at room temperature for 20 h. The residual H2 was
carefully released into a hood, and 5% Pd/C (3.0 g, 6% wt/
wt based on substrate 6) and TsOH·H2O (1.82 g,
0.0095 mol) were added slowly into the reaction mixture.
The autoclave was again purged 3 times with H2 and finally
pressured to 2 atm, and allowed to react further for 24 h.
The hydrogen gas was released into a hood, and the mixture
was filtered through a short pad of celite. The solvent of the
filtrate was removed under vacuum, and the residue was pu-
rified by recrystallization from the ethyl acetate/petroleum
ether mixed solvent to afford (R,R,R)-4b as a white crystal-
line solid; yield: 24.8 g (>99% ee).
References
[1] For recent reviews, see: a) M. Brasholz, S. Sçrgel, C.
Azap, H.-U. Reißig, Eur. J. Org. Chem. 2007, 3801; b) J.
Sperry, Z. E. Wilson, D. C. K. Rathwell, M. A. Brimble,
Nat. Prod. Rep. 2010, 27, 1117. For selected examples,
see: c) Y.-C. Hu, X.-F. Wu, S. Gao, S.-S. Yu, Y. Liu, J.
Qu, J. Liu, Y.-B. Liu, Org. Lett. 2006, 8, 2269; d) P.-L.
Huang, S.-J. Won, S.-H. Day, C.-N. Lin, Helv. Chim.
Acta 1999, 82, 1716; e) X. Zhang, L. Shan, H. Huang,
X. Yang, X. Liang, A. Xing, H. Huang, X. Liu, J. Su,
W. Zhang, J. Pharm. Biomed. Anal. 2009, 49, 715; f) A.
Trani, C. Dallanoce, G. Panzone, F. Ripamonti, B. P.
Goldstein, R. Ciabatti, J. Med. Chem. 1997, 40, 967;
g) C. Puder, S. Loya, A. Hizi, A. Zeeck, Eur. J. Org.
Chem. 2000, 729; h) T. Ueno, H. Takahashi, M. Oda,
M. Mizunuma, A. Yokoyama, Y. Goto, Y. Mizushina,
K. Sakaguchi, H. Hayashi, Biochemistry 2000, 39, 5995.
[2] M. D. Weingarten, J. A. Sikorski, N. Raymond, L. Ni,
Z. Ye, C. Q. Meng, Patent WO 2008/140781A1, Novem-
ber 20, 2008.
[3] a) Z. Freixa, M. S. Beentjes, G. D. Batema, C. B. Diele-
man, G. P. F. van Strijdonck, J. N. H. Reek, P. C. J.
Kamer, J. Fraanje, K. Goubitz, P. W. N. M. van Leeu-
wen, Angew. Chem. 2003, 115, 1322; Angew. Chem. Int.
Ed. 2003, 42, 1284; b) Z. Freixa, P. C. J. Kamer, M.
Lutz, A. L. Spek, P. W. N. M. van Leeuwen, Angew.
Chem. 2005, 117, 4459; Angew. Chem. Int. Ed. 2005, 44,
4385; c) C. Jimꢃnez-Rodrꢄguez, F. X. Roca, C. Bo, J.
Benet-Buchholz, E. C. Escudero-Adꢅn, Z. Freixa,
P. W. N. M. van Leeuwen, Dalton Trans. 2006, 268;
d) X. Sala, E. J. G. Suꢅrez, Z. Freixa, J. Benet-Buch-
holz, P. W. N. M. van Leeuwen, Eur. J. Org. Chem.
2008, 6197; e) J. Li, G. Chen, Z. Wang, R. Zhang, X.
Zhang, K. Ding, Chem. Sci. 2011, 2, 1141; f) X. Wang,
F. Meng, Z. Han, Y. Chen, L. Liu, Z. Wang, K. Ding,
Angew. Chem. 2012, 124, 9410; Angew. Chem. Int. Ed.
2012, 51, 9276; g) X. Jia, Z. Wang, C. Xia, K. Ding,
Chem. Eur. J. 2012, 18, 15288; h) X. Jia, Z. Wang, C.
Procedure for Large-Scale Preparation of the SKP
Ligand (R,R,R)-6a (Method A)
To a 500-mL three-neck flask equipped with magnetic stir-
ring bar were added (R,R,R)-4b (12 g, 0.036 mol) and KPPh2
(168 mL, 0.084 mol, 0.5M in THF) under a stream of argon.
2906
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 2900 – 2907

Practical Asymmetric Catalytic Synthesis of Spiroketals and Chiral Diphosphine Ligands
Xia, K. Ding, Catal. Sci. Technol. 2013, 3, 1901; i) O.
Jacquet, N. D. Clement, C. Blanco, M. M. Belmonte, J.
Benet-Buchholz, P. W. N. M. Van Leeuwen, Eur. J. Org.
Chem. 2012, 4844; j) Z. Cao, X. Wang, T. Chen, X.
Zhao, J. Zhou, K. Ding, J. Am. Chem. Soc. 2013, 135,
8197.
H. U. Reissig, Angew. Chem. 2012, 124, 9624; Angew.
Chem. Int. Ed. 2012, 51, 9486.
[12] Z. Sun, G. A. Winschel, A. Borovika, P. Nagomy, J.
Am. Chem. Soc. 2012, 134, 8074.
[13] H. Wu, Y.-P. He, L.-Z. Gong, Org. Lett. 2013, 15, 460.
[14] a) Z. Han, Z. Wang, X. Zhang, K. Ding, Angew. Chem.
2009, 121, 5449; Angew. Chem. Int. Ed. 2009, 48, 5345;
b) Y. Zhang, Z. Han, F. Li, K. Ding, A. Zhang, Chem.
Commun. 2010, 46, 156; c) Z. Han, Z. Wang, K. Ding,
Adv. Synth. Catal. 2011, 353, 1584; d) J. Shang, Z. Han,
Y. Li, Z. Wang, K. Ding, Chem. Commun. 2012, 48,
5172; e) J.-H. Xie, Q.-L. Zhou, Acta Chim. Sinica 2012,
70, 1427.
[15] The spiro backbone has been recognized as a privileged
structure for the construction of chiral ligands; see:
a) Privileged Chiral Ligands and Catalysts, (Ed.: Q.-L.
Zhou), Wiley-VCH, Weinheim, 2011; b) A. S. C. Chan,
W. Hu, C.-C. Pai, C.-P. Lau, Y. Jiang, A. Mi, M. Yan, J.
Sun, R. Lou, J. Deng, J. Am. Chem. Soc. 1997, 119,
9570; c) J.-H. Xie, Q.-L. Zhou, Acc. Chem. Res. 2008,
41, 581; d) K. Ding, Z. Han, Z. Wang, Chem. Asian J.
2009, 4, 32; e) G. B. Bajracharya, M. A. Arai, P. S. Ko-
ranne, T. Suzuki, S. Takizawa, H. Sasai, Bull. Chem.
Soc. Jpn. 2009, 82, 285.
[16] M. Schelhaas, H. Waldmann, Angew. Chem. 1996, 108,
2192; Angew. Chem. Int. Ed. Engl. 1996, 35, 2056.
[17] a) S. Murahashi, H. Takaya, Acc. Chem. Res. 2000, 33,
225; b) X. Li, A. R. Chianese, T. Vogel, R. H. Crabtree,
Org. Lett. 2005, 7, 5437; c) G. Onodera, T. Toeda, N.
Toda, D. Shibagishi, R. Takeuchi, Tetrahedron 2010, 66,
9021; d) L. D. Field, B. A. Messerle, S. L. Wren, Orga-
nometallics 2003, 22, 4393; e) J. H. H. Ho, R. Hodgson,
J. Wagler, B. A. Messerle, Dalton Trans. 2010, 39, 4062.
For examples of transition metal complex-catalyzed
acetalizations, see: f) F. Gorla, L. M. Venanzi, Helv.
Chim. Acta 1990, 73, 690; g) M. Cataldo, E. Nieddu, R.
Gavagnin, F. Pinna, G. Strukul, J. Mol. Catal. A 1999,
142, 305; h) Q. Jiang, H. Rꢆegger, L. M. Venanzi,
Inorg. Chim. Acta 1999, 290, 64; i) M. Sꢆlꢆ, L. M. Ven-
anzi, Helv. Chim. Acta 2001, 84, 898; j) C. Crotti, E.
Farnetti, N. Guidolin, Green Chem. 2010, 12, 2225.
[18] a) Y. Zhu, Y. Fan, K. Burgess, J. Am. Chem. Soc. 2010,
132, 6249; b) P. Cheruku, J. Diesen, P. G. Andersson, J.
Am. Chem. Soc. 2008, 130, 5595; c) P. Cheruku, S.
Gohil, P. G. Andersson, Org. Lett. 2007, 9, 1659; d) Y.
Zhu, K. Burgess, Adv. Synth. Catal. 2008, 350, 979;
e) M. C. Perry, X. Cui, M. T. Powell, D.-R. Hou, J. H.
Reibenspies, K. Burgess, J. Am. Chem. Soc. 2003, 125,
113; f) G. S. McGrady, G. Guilera, Chem. Soc. Rev.
2003, 32, 383; g) X. Qi, L. Liu, Y. Fu, Q. Guo, Organo-
metallics 2006, 25, 5879.
[4] For reviews, see: a) F. Perron, K. F. Albizati, Chem.
Rev. 1989, 89, 1617; b) K. T. Mead, B. N. Brewer, Curr.
Org. Chem. 2003, 7, 227; c) J. E. Aho, P. M. Pihko, T. K.
Rissa, Chem. Rev. 2005, 105, 4406.
[5] For examples of aromatic spiroketal synthesis via
Brønsted or Lewis acid catalyzed cyclization of a bi-
sphenolic dihydroxyketone intermediate, see: a) T.
Tanaka, M. Miyayguchi, R. K. Mochisuki, S. Tanaka,
M. Okanoto, Y. Kitajima, T. Miyazaki, Heterocycles
1987, 25, 463; b) T. Capecchi, C. B. D. Koning, J. P. Mi-
chael, Tetrahedron Lett. 1998, 39, 5429; c) T. Capecchi,
C. B. D. Koning, J. P. Michael, J. Chem. Soc. Perkin
Trans. 1 2000, 2681; d) K. Y. Tsang, M. A. Brimble, J. B.
Bremner, Org. Lett. 2003, 5, 4425; e) K. Y. Tsang,
M. A. Brimble, Tetrahedron 2007, 63, 6015; f) S. P.
Waters, M. W. Fennie, M. C. Kozlowski, Tetrahedron
Lett. 2006, 47, 5409; g) S. Sçrgel, C. Azap, H.-U. Reis-
sig, Org. Lett. 2006, 8, 4875; h) M. A. Brimble, C. L.
Flowers, M. Trzoss, K. Y. Tsang, Tetrahedron 2006, 62,
5883; i) Y. Xin, H. Jiang, J. Zhao, S. Zhu, Tetrahedron
2008, 64, 9315; j) C. Venkatesh, H.-U. Reissig, Synthesis
2008, 3605; k) D. C. K. Rathwell, S.-H. Yang, K. Y.
Tsang, M. A. Brimble, Angew. Chem. 2009, 121, 8140;
Angew. Chem. Int. Ed. 2009, 48, 7996; l) F. Wang, M.
Qu, X. Lu, F, Chen, F. Chen, M. Shi, Chem. Commun.
2012, 48, 6259.
[6] For selected examples of aromatic spiroketal synthesis
via ring closure of the hydroxyl enol ethers, see:
a) D. H. Qin, R. X. Ren, T. Siu, C. S. Zheng, S. J. Dani-
shefsky, Angew. Chem. 2001, 113, 4845; Angew. Chem.
Int. Ed. 2001, 40, 4709; b) W. Wei, L. Li, X. Lin, H. Li,
J. Xue, Y. Li, Org. Biomol. Chem. 2012, 10, 3494.
[7] For examples of aromatic spiroketal synthesis via
hetero-Diels–Alder reactions, see: a) G. Zhou, D.
Zheng, S. Da, Z. Xie, Y. Li, Tetrahedron Lett. 2006, 47,
3349; b) X. Li, J. J. Xue, C. S. Huang, Y. Li, Chem.
Asian J. 2012, 7, 903. For a review, see: c) M. A. Rizza-
casa, A. Pollex, Org. Biomol. Chem. 2009, 7, 1053.
[8] For examples of other miscellaneous routes to aromatic
spiroketals, see: a) S. Akai, K. Kakiguchi, Y. Naka-
mura, I. Kuriwaki, T. Dohi, S. Harada, O. Kubo, N.
Morita, Y. Kita, Angew. Chem. 2007, 119, 7602; Angew.
Chem. Int. Ed. 2007, 46, 7458; b) K.-L. Wu, E. V. Mer-
cado, T. R. R. Pettus, J. Am. Chem. Soc. 2011, 133,
6114; c) C. C. Lindsey, K. L. Wu, T. R. R. Pettus, Org.
Lett. 2006, 8, 2365; d) Y. Zhang, J. Xue, Z. Xin, Z. Xie,
Y. Li, Synlett 2008, 940; e) P. J. Choi, D. C. K. Rathwell,
M. A. Brimble, Tetrahedron Lett. 2009, 50, 3245.
[19] a) J. M. Brunel, Chem. Rev. 2007, 107, PR1; b) M. Shi-
basaki, N. Yoshikawa, Chem. Rev. 2002, 102, 2187; c) J.
Inanaga, H. Furuno, T. Hayano, Chem. Rev. 2002, 102,
2211; d) Y. Chen, S. Yekta, A. Yudin, Chem. Rev. 2003,
103, 3155.
[20] O. Herd, A. Hessler, K. P. Langhans, O. Stelzer, W. S.
Sheldrick, N. Weferling, J. Organomet. Chem. 1994,
475, 99.
[9] A. K. Franz, N. V. Hanhan, N. R. Ball-Jones, ACS
Catal. 2013, 3, 540.
[10] X. Wang, Z. Han, Z. Wang, K. Ding, Angew. Chem.
2012, 124, 960; Angew. Chem. Int. Ed. 2012, 51, 936.
ˇ
´
[11] a) I. Coric, B. List, Nature 2012, 483, 315. For a highlight
of the works reported in refs.[10,11a], see: b) M. Wilsdorf,
Adv. Synth. Catal. 2013, 355, 2900 – 2907
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2907