Stereogenic phosphorus-induced diastereoselective formation of chiral carbon during nucleophilic addition of chiral H-P species to aldehydes or ketones

Article abstract of DOI:10.1002/asia.201301650

P,C-Stereogenic α-hydroxyl phosphinates or phosphine oxides were prepared from the additions of (R_P)-phosphinate to ketones or (R _P)-phosphine oxide to aldehydes, respectively, catalyzed by bases at room temperature in up to >99:1 di

Full text of DOI:10.1002/asia.201301650

FULL PAPER
DOI: 10.1002/asia.201301650
Stereogenic Phosphorus-Induced Diastereoselective Formation of Chiral
À
Carbon during Nucleophilic Addition of Chiral H P Species to Aldehydes or
Ketones
He Zhang,[a] Yong-Ming Sun,[a] Lan Yao,[a] Si-Yu Ji,[a] Chang-Qiu Zhao,*[a] and
Li-Biao Han[b]
Abstract: P,C-Stereogenic a-hydroxyl phosphinates or phosphine oxides were pre-
pared from the additions of (RP)-phosphinate to ketones or (RP)-phosphine oxide
to aldehydes, respectively, catalyzed by bases at room temperature in up to >99:1
diasteromeric ratio (d.r.P/d.r.C) and 99% yields. The diastereoselectivity was in-
duced by reversible equilibrium and different stabilities between two diastereo-
mers of adduct, which was caused by the spatial interaction between menthoxyl or
menthyl to alkyl groups of aldehydes or ketones.
Keywords: aldehydes · asymmetric
synthesis diastereoselectivity
phosphorus · ketones
·
·
Introduction
Optically active phosphorus compounds have attracted ex-
tensive attention in recent years because of their potential
application as biologically active substances[1] and precursors
of ligands for asymmetric catalysis.[2] Among them, a-hy-
droxyl phosphoric derivatives have particular value because
of their utility as the inhibitors of HIV protease[3] or
rennin,[4] and as g-aminobutyric acid (GABA) antagonists[5]
Scheme 1. Comparison of reported results to our current work.
or herbicides.[6] The addition of P H species to carbon–
À
oxygen double bonds, known as the Pudovik reaction,[7] was
traditionally used for the preparation of a-hydroxyl phos-
phoric compounds. The relevant stereoselective approaches
were extensively developed by several research groups, and
were usually committed to the formation of C-stereogenic
applied to the Pudovik reaction, both carbon and phospho-
rus chiral centers could be generated, thereby deriving up to
À
four possible stereomers by means of cleavage of the P H
[10]
À
bond and formation of the P C bond. Owing to the poor
À
phosphoric derivatives by means of addition of nonchiral P
induction of the P-stereogenic center to the generation of
chiral carbon,[9b,11] to the best of our knowledge, the simulta-
neous formation of carbon and phosphorus chiral centers
with excellent stereoselectivity has scarcely been studied.
Recently, Montchamp’s group reported P,C-stereogenic a-
hydroxyl phosphinates in 94% diastereomeric excess (de)
by means of Wittig rearrangement.[12] On the basis of the re-
H species to prochiral aldehydes or ketones by employing
asymmetric catalysts that concerned heavy metals or ligands
that are accessible with difficulty (Scheme 1).[8] The synthe-
sis of a-hydroxyl phosphoric compounds that contain both
carbon and phosphorus chiral centers is quite limited.
À
P-Stereogenic P H species have attracted growing atten-
À
tion because of their novel applications in the construction
versible equilibrium for the addition of P H species to alde-
[9]
of asymmetric P C bonds. When these compounds were
hydes or ketones under alkali conditions,[13] it was hoped
that the diastereomers of the adduct would show different
thermodynamic stabilities that lead to a more stable one
being formed predominantly. Herein we disclose the results
of additions to aldehydes or ketones with (RP)-O-(À)-
menthyl H-phenylphosphinate (1a)[9c,e] or (RP)-(À)-menthyl
phenylphosphine oxide (1b).[14] In these reactions, the P,C-
stereogenic a-hydroxyl phosphinates or phosphine oxides
were readily obtained in up to >99:1 diasteromeric ratio
(d.r.) under mild conditions.
À
[a] H. Zhang,+ Y.-M. Sun,+ L. Yao, S.-Y. Ji, Prof. Dr. C.-Q. Zhao
College of Chemistry and Chemical Engineering
Liaocheng University, Liaocheng, Shandong 252059 (China)
Fax : (+86)6359239121
E-mail: literabc@hotmail.com
[b] Prof. Dr. L.-B. Han
National Institute of Advanced Industrial Science
and Technology (AIST), Tsukuba, Ibaraki 305-8565 (Japan)
[+] The authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201301650.
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Chang-Qiu Zhao et al.
Results and Discussion
racemic 2-methyl cyclohexanone. For prochiral trifluoroace-
tophenone, the O-phosphorylated product was detected in
four stereomers when catalyzed by K2CO3; these were gen-
erated from different configurations on both the phosphorus
and carbon atoms. In the absence of base, C-phosphorylated
4l was formed predominately in two stereomers, which were
derived from the configuration on the a-carbon atom
(Table 1, entry 12).
Potassium carbonate did not show catalytic activity
toward the addition of 1b to aldehydes at room tempera-
ture. When catalyzed by KOH in DMSO or Ca(OH)2 in
DMF, the reactions occurred in excellent yields and selectiv-
ities to afford a-hydroxyl phosphine oxides 6. On the basis
of 31P NMR spectroscopy, the peaks for major diastereomers
of 6, which were confirmed to have RPSa-C structure by X-
ray crystallography, were located at upper field relative to
minor ones. As seen in Table 2, the addition of 1b to various
aromatic and aliphatic aldehydes was examined. In most
cases, the formation of 6 reached yields of 99% and up to
>99:1 d.r.C (RPSa-C-/RPRa-C-6/6’). The reaction of some aro-
matic aldehydes, respectively, catalyzed by two bases, gave
similar yields and d.r.C. Some ortho-substituted benzalde-
hydes gave poor yields of 6 when catalyzed by KOH; they
suffered from the side reaction that generated 5 (Table 1,
entry 10–13 and Scheme 2). The side reaction could be clear-
Among the base-promoted additions of 1a or 1b to alde-
hydes 2 or ketones 3—in addition to the combinations of 1a
to 2 that afforded the adduct in poor selectivity[10,15] and 1b
to 3 that cannot occur at room temperature—the reactions
of 1a to 3 and 1b to 2 exhibited some diastereoselectivity.
We found that K2CO3 effectively catalyzed the addition of
1a to ketones in DMSO to afford a-hydroxyl phosphinates
4 stereospecifically with retention of the configuration on
the phosphorus atoms.[9,12]
As seen in Table 1, the reactions of most p-substituted
acetophenones with 1a gave 4 in excellent yields and more
than 90:10 d.r.C. The meta-substituted acetophenones afford-
Table 1. Addition to ketones 3 with 1a.
[a]
Entry
R1-CO-R2, 3
t [h]
Yield[a] [%]
d.r.C
1
2
3
4
5
6
7
8
Ph, Me
40
24
68
54
60
40
72
90
96
88
24
76
107
48
24
44
24
96
65
24
100
16
4a, 75 (37)
4b, 97 (74)
4c, 90 (71)
4d, 87 (82)
4e, 70 (50)
4 f, 48 (20)
4g’, 71 (40)
4h, 93 (80)
4i, 94 (81)
4j, 87 (69)
4k, 35
90:10
98:2
99:1
84:16
67:33
84:16
12:88
99:1
p-BrC6H4, Me
p-ClC6H4, Me
p-FC6H4, Me
m-BrC6H4, Me
p-NO2C6H4, Me
m-NO2C6H4, Me
p-CH3C6H4, Me
p-CH3OC6H4, Me
p-PhC6H4, Me
m-NH2C6H4, Me
Ph, CF3
9
99:1
97:3
10
11
12
13
14
15
16
17
18
19
20
21
22
63:37
36:64[b,c]
53:47[c]
46:54[c]
–
–
–
–
4l, 97 (65)
4m, 47 (34)
4n, 19
2-furyl, Me
1-naphyl, Me
A
4o, 99 (92)
4p, 98 (90)
4q, 99 (88)
4r, 54 (42)
4s, 98 (43)
4t, 83 (22)
4u, 54 (41)
4v, 90 (76)
N
Scheme 2. Formation of 5 by means of Phospha–Brook rearrangement.
Me, Me
Et, Et
Et, Me
iBu, Me
27:73[c]
68:32
51:49[c]
5:50:7:38[c]
ly avoided when Ca(OH)2 was employed as catalyst, except
for the case of salicylaldehyde. As seen in entry 13 of
Table 1, Ca(OH)2 slightly improved the formation of 6 to
31% yield, which was decomposed upon purification with
preparative TLC. The yields for the reactions of aliphatic al-
dehydes were lower than that of aromatic aldehydes, and in
some cases they did not reach 99%. For paraldehyde, the
d.r.C was poor when catalyzed by KOH, and it was improved
to >99:1 when catalyzed by Ca(OH)2.
iPr, Me
2-Me-cyclohexanone
[a] Typical procedure: 1a (0.36 mmol) and 3 (0.36 mmol) were stirred in
DMSO (1 mL) in the presence of K2CO3 (25% molar) at RT. Yield and
d.r.C were estimated by 31P NMR spectroscopy, and isolated yield is pre-
sented in parentheses. Values of d.r.C were assigned as 4/4’ (SPRa-C/SPSa-C
)
except for unconfirmed diastereomers. [b] The reaction was carried out
in diethyl ether without base. [c] The structures of diastereomers were
not confirmed.
The major side reaction for both additions of 1a to 3 and
1b to 2 was the formation of 5 by means of Phospha–Brook
rearrangement.[16] As seen in Scheme 2, ortho-substituted or
electron-withdrawing group (EWG)-containing aromatic al-
dehydes or ketones, especially when catalyzed by a stronger
base or when the reaction was carried out under heating
conditions, tended to form 5. For example, o-chloroaceto-
phenone and 1a afforded trace 4 under typical conditions in
Table 1. At elevated temperature, 5a was obtained as the
major product.
ed 4 in poor to moderate yields and poor d.r.C. Among
them, m-nitroacetophenones even showed reversed selectivi-
ty (Table 1, entry 7). The reactions for some ketones such as
ortho-substituted acetophenones, p-hydroxyacetophenone,
a-tetralone, and acetylferrocene cannot take place, and for
some ketones such as p-aminoacetophenone, 2-acetyl furan,
and 1-acetylnaphthene gave poor yields. Acyclic aliphatic
ketones gave moderate yields of 4 but in poor d.r.C. As
shown in entry 22 of Table 1, the reaction afforded four ster-
eomers in the ratio 5:50:7:38, which were generated from
The 59:41 d.r.C of 4b/4b’, which was isolated from the re-
action of 1a to 3b for 30 minutes, was improved to 94:6 and
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Chang-Qiu Zhao et al.
Table 2. Addition to aldehydes 2 with 1b.
Table 2), and acquiring the best d.r.C took a shorter
time in the case of the former.
On the basis of these consequences, we believed
that both additions of 1a to 3 and 1b to 2 were re-
versible, and the thermodynamic stabilities for the
two diastereomers 4/4’ or 6/6’ were different. In the
presence of base, a more unstable 4’ or 6’ would
have a stronger tendency to be converted back to
1 and 2/3 through a reversible equilibrium, which
would then be converted to 4/6 after enough time.
The P-retention additions for both 1a and 1b, as
well as the Ra-C and Sa-C configuration for 4 and 6,
respectively, were confirmed by crystallography. In
the one-dimensional chain structures (as seen in the
Supporting Information), the a-hydroxyl and the
P=O bond are in an anti-periplanar position in the
cross conformation of 4 and 6 because of the exis-
tence of intermolecular hydrogen bonds. As for 4
generated from acetophenones, the stabilities of the
two diastereomers are controlled by the repulsion
between menthoxyl to aryl or methyl of the aceto-
phenone moieties. For para-substituted acetophe-
nones, it was observed that the isopropyl group of
menthyl faced toward the plane of the benzene
ring, and two methyl groups of isopropyl were ori-
ented in the direction far toward benzene ring. In
this manner, the spatial interaction between isopro-
pyl and aryl might be reduced (Figure 1). For meta-
substituted acetophenones, the increased volume of
the aryl group resulted in strong repulsion toward
methoxyl and poor selectivities for the formation of
4. In some cases, 4’ was formed as major diastereo-
mer (Table 1, entry 7). The ortho-substituted aryls
have larger volumes, and the reaction of the corre-
sponding acetophenones cannot occur under typical
[a]
Entry
R1CHO, 2
Base
t [h]
Yield[a] [%] 6
d.r.C
Yield [%] 5
1
2
3
C6H5
A
A
B
A
B
B
A
B
A
B
A
A
B
A
A
A
A
B
A
B
B
A
B
A
B
B
A
B
A
24
23
17
24
11
11
23
11
5
11
24
24
10
5[b]
24
23
24
11
24
12
11
25
11
24
5
6a, >99 (80)
6b, >99 (81)
6c, 53 (40)
6d, >99
6d, >99 (75)
6e, >99 (86)
6 f, >99
6 f, >99 (78)
6g, >99 (85)
6g, 80
6h, 98 (80)
6i, >99 (81)
3
>99:1
98:2
82:18
98:2
>99:1
95:5
98:2
>99:1
>99:1
96:4
98:2
97:3
–
–
–
–
–
–
–
–
–
–
–
–
p-ClC6H4
p-O2NC6H4
p-MeC6H4
4
5
6
p-iPrC6H4
p-MeOC6H4
p-Me2NC6H4
7
8
9
o-FC6H4
o-ClC6H4
5b, 97 (80)
–
–
5c, 27
–
5d, 58
5e, 42
o-BrC6H4
6j, >99
98:2
>99:1
98:2
>99:1
95:5
10
11
12
6j, 98 (78)
6k, 63 (50)
6l, >99 (78)
6l, 42
31
5
6m, >99 (79)
6n, >99 (78)
6o, 93 (74)
6p, >99 (85)
6q, 77
6q, 80 (65)
6r, >99 (83)
6s, 87
o-O2NC6H4
o-MeOC6H4
o-HOC6H4
98:2
13
5e, 95 (83)
14
15
16
17
m-BrC6H4
3,4,5-(MeO)3C6H2
iPr
ACHTUNGTRENNUNG(Me2)CHCH2
nC11H23
>99:1
>99:1
>99:1
98:2
58:42
>99:1
–
–
–
–
–
–
–
–
–
–
18
19
20
23
41
16
36
H, (CH2O)n
Me, (CHMeO)3
60:40
>99:1
6s, 90 (75)
[a] Typical procedure: 1b (0.38 mmol) and 2 (0.38 mmol) were stirred in solvent
(0.5 mL) in the presence of 25% molar base. A) Ca(OH)2 was used in DMF. B) KOH
was used in DMSO. Yield and d.r.C were estimated by 31P NMR spectroscopy, and the
isolated yield is presented in parentheses. Values of d.r.C were assigned as 6/6’ (RPSa-C
RPRa-C). [b] Three molar equivalents of aldehyde were used.
/
97:3 when the mixture was stirred with K2CO3 for 1.5 and
5 hours, respectively. At the same time, a trace amount of
1a was detected by 31P NMR spectroscopy. In fact, the reac-
tion of 1a to 3b was completed within 1 hour, and pro-
longed reaction times only improved the ratio of 4b/4b’. As
seen in Scheme 3, d.r.C of 4b/4b’ was observed in as 60:40,
90:10, and 97:3 when 1a and 3b were stirred for 0.25, 10,
and 24 hours, respectively. A similar improvement in d.r.C
over time was also observed for the addition of 1b to 2
when catalyzed by KOH or Ca(OH)2 (entry 10 and 18 of
Figure 1. Supposed conformation of 4/4’ and 6/6’.
conditions in Table 1. In these cases, only 5 was formed by
means of Phospha–Brook rearrangement at elevated tem-
perature (Scheme 2). Density functional calculations of 4b/
4b’ and 4g/4g’ showed that 4b and 4g’ have lower energy
than their associated diastereomers, respectively, which was
consistent with the results in Table 1 (as shown in the Sup-
porting Information).
Similarly, the menthyl close to R also resulted in the insta-
bility of 6’. The better diastereoselectivity for the reaction of
1b to 3 over 1a to 2 could be ascribed to the fact that the
stereogenic phosphorus atom in 1b is more bulky than that
in 1a, which could also explain the poor selectivity for the
Scheme 3. Improvement of d.r.C for 4b/4b’ over reaction time.
Chem. Asian J. 2014, 9, 1329 – 1333
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Chang-Qiu Zhao et al.
Typical Procedure for Preparation of a-Hydroxyphosphine Oxides 6 by
Means of Addition of 1b to Aldehydes 2
addition of 1a to 2 and the poor reactivity for the addition
of 1b to 3.
After our work was completed, we noticed that Couzijn
and Minnaard et al. reported the addition of P-stereogenic
tert-butylphenylphosphine oxide to aldehydes in the pres-
ence of base, diastereoselectively affording a-hydroxyphos-
phine oxides in >20:1 d.r.[17] Their work confirmed the re-
versible equilibrium of the addition and revealed the con-
version of less stable diastereomers to more stable ones by
undertaking the reaction at 50 or 808C. Our results in
Table 2 and Scheme 2 showed that elevated temperatures
can lead to side reactions such as Phospha–Brook rearrange-
Aldehydes 2 (0.38 mmol) and calcium hydroxide (7.6 mg, 0.10 mmol)
were added in turn to a solution of RP-(À)menthylphenylphosphine oxide
1b (0.1 g, 0.38 mmol) in DMF (0.5 mL) (method A; for method B, the
same molar amount of potassium hydroxide was used in the same
volume of DMSO). The mixture was stirred at room temperature for
about 24 h, and the reaction was monitored with 31P NMR spectroscopy (
ꢀ0.1 mL suspension of reaction mixture dissolved in chloroform
(0.4 mL)). After the reaction finished, acetic acid (0.1 mL) was added to
the mixture, followed by the addition of methanol (3 mL). The mixture
was filtered through silica gel and concentrated under vacuum. The resi-
due was purified by recrystallization with MeOH/Et2O to afford pure 6.
(RP)-(À)-Menthyl[(S)-hydroxyACHTUNGTRNE(NUNG phenyl)methyl]phenylphosphine oxide
À
ment or racemization of P H species, which might be used
(6a)
to explain the higher yields and diasteromeric ratio in our
Compound 6a was obtained from method A as white solid (139 mg,
yield: 80%). M.p. 133.5–1358C. 31P NMR (162 MHz, CDCl3): d=
41.12 ppm; 1H NMR (400 MHz, CDCl3): d=7.58–7.46 (m, 2H), 7.40 (t,
J=7.5 Hz, 1H), 7.27 (d, J=9.7 Hz, 3H), 7.10 (dt, J=14.1, 6.8 Hz, 3H),
6.92 (d, J=7.4 Hz, 2H), 5.35 (dd, J=10.4, 3.8 Hz, 1H), 3.08 (td, J=
22.2 Hz, 1H), 2.39 (s, 2H), 1.73 (s, 1H), 1.64–1.37 (m, 2H), 1.37–1.15 (m,
3H), 1.14–0.93 (m, 2H), 0.93–0.81 (m, 3H), 0.72 (d, J=6.7 Hz, 3H),
0.24 ppm (d, J=6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3): d=137.20,
131.90–131.00 (m), 128.38–127.37 (m), 127.10 (d, J=3.9 Hz), 71.15 (d, J=
84.1 Hz), 43.20 (d, J=3.9 Hz), 37.68 (dd, J=64.1, 8.1 Hz), 34.36 (d, J=
34.9 Hz), 33.42 (d, J=13.1 Hz), 28.21 (d, J=3.2 Hz), 24.88 (d, J=
11.9 Hz), 22.91, 21.63, 15.37 ppm; elemental analysis calcd (%) for
C23H31O2P: C 74.57, H 8.43; found: C 74.39, H 8.41.
addition of 1b to 3 at room temperature.
Conclusion
In summary, base-catalyzed addition of 1 to aldehydes or
ketones was a stability-controlled diastereoselective reac-
tion. The less stable diastereomers of the adduct can be con-
verted to more stable ones by means of reversible equilibri-
um and prolonged reaction time. Although thermodynami-
cally controlled diastereoselective reactions are widely ap-
plied in asymmetric synthesis, the similar P-involving reac-
tion that utilizes a reversible equilibrium is, to the best of
our knowledge, quite rare. Our research supplied a conven-
ient and useful method for the simultaneous formation of
both phosphorus and carbon chiral centers.
Acknowledgements
The authors acknowledge the financial support of the Natural Science
Foundation of China (grant no. 20772055).
Experimental Section
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Compounds, Vol. 1 (Ed.: F. R. Hartley), Wiley, New York, 1990,
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Typical Procedure for Preparation of a-Hydroxyphosphinates 4 by Means
of Addition of 1a to Ketones 3
Ketone 3 (0.368 mmol) and potassium carbonate (0.013 g, 0.092 mmol)
were added in turn to a solution of RP-(À)menthyl phenylphosphinate 1a
(0.103 g, 0.368 mmol) in DMSO (1 mL). The mixture was stirred at room
temperature for 24 to 100 h, and the reaction was monitored with
31P NMR spectroscopy (ꢀ0.1 mL suspension of reaction mixture dis-
solved in 0.5 mL chloroform). After the reaction finished, water (2 mL)
was added to the mixture, and the solid was filtered and dried in air. The
crude product was recrystallized with CH2Cl2/petroleum ether (PE) to
afford pure 4.
(S)-(À)-Menthyl [(R)-1-(4-bromophenyl)-1-
hydroxyethyl]phenylphosphinate (4b)
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Compound 4b was obtained as a white solid (0.126 g, yield: 74%). M.p.
176.2–177.38C. H NMR (400 MHz, CDCl3): d=7.50 (dd, J=16.1, 8.1 Hz,
1
3H), 7.39 (d, J=8.4 Hz, 2H), 7.31 (t, J=9.8 Hz, 4H), 4.40–4.16 (m, 1H),
3.78 (br, 1H), 2.05–1.84 (m, 1H), 1.77 (d, J=14.1 Hz, 3H), 1.76–1.55 (m,
Hz, 4H), 1.35 (t, J=11.5 Hz, 1H), 1.21 (br, 1H), 1.04–0.82 (m, 5H),
0.82–0.57 ppm (m, 6H); 31P NMR (162 MHz, CDCl3): d=38.31 ppm (s);
13C NMR (101 MHz, CDCl3): d=140.56 (s), 133.70 (d, J=8.3 Hz), 132.43
(s), 130.96 (s), 129.86 (s), 128.23 (s), 127.88 (d, J=11.8 Hz), 121.56 (s),
78.04 (d, J=7.7 Hz), 75.48 (s), 74.35 (s), 49.11 (d, J=4.5 Hz), 43.27 (s),
34.16 (s), 31.65 (s), 25.48 (s), 24.91 (s), 22.74 (s), 22.02 (s), 21.31 (s),
15.42 ppm (s); elemental analysis calcd (%) for C24H32O3PBr: C 60.13, H
6.73; found: C 60.02, H 6.81.
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Received: December 13, 2013
Revised: January 6, 2014
Published online: March 3, 2014
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