Kinetic resolution of racemic α-hydroxyphosphonates by asymmetric esterification using achiral carboxylic acids with pivalic anhydride and a chiral acyl-transfer catalyst

Article abstract of DOI:10.1039/c3cc44293d

A practical protocol is developed to directly provide chiral α-acyloxyphosphonates and α-hydroxyphosphonates from (±)-α-hydroxyphosphonates utilizing the transacylation process to generate the mixed anhydrides from acid components and pivalic anhydride in the presence of organocatalysts (s-value = 33-518).

Full text of DOI:10.1039/c3cc44293d

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Kinetic resolution of racemic a-hydroxyphosphonates
by asymmetric esterification using achiral carboxylic
acids with pivalic anhydride and a chiral acyl-transfer
catalyst†
Cite this: Chem. Commun., 2013,
49, 10700
Received 7th June 2013,
Accepted 21st September 2013
DOI: 10.1039/c3cc44293d
Isamu Shiina,* Keisuke Ono and Takayoshi Nakahara
www.rsc.org/chemcomm
A practical protocol is developed to directly provide chiral a-acyloxy- the mixed anhydride (MA) method and successfully determined
phosphonates and a-hydroxyphosphonates from (Æ)-a-hydroxy- the preferable transition structures required to form the desired
phosphonates utilizing the transacylation process to generate the chiral (R)-esters starting from diphenylacetic acid with secondary
mixed anhydrides from acid components and pivalic anhydride in (R)-alcohols using density functional theory (DFT) calculations.4b
the presence of organocatalysts (s-value = 33–518).
It was revealed that the conformation of the transition structure
(ts-(R)) to form methyl (R)-2-(diphenylacetoxy)propanoate starting
Chiral a-hydroxyphosphonates and a-amino phosphonates have from methyl (R)-lactate via the intermediary dihydroimidazolium
attracted considerable attention because of their potential biological salt I as shown in Fig. 1 is strongly restricted by an attractive
activities, including their antitumor and enzyme inhibitory effects.1 interaction between the oxygen in the ester carbonyl group and
In addition, it has been shown that several peptide analogues, the positive electronic charge on the face of intermediate I during
such as a-hydroxyphosphonate moieties, function as HIV protease the bond-forming step.4b,c,7 On the basis of analysis of these
inhibitors.1g–j Therefore, enzymatic methods for the preparation of calculated structures, we expected that (i) an attractive interaction
chiral a-hydroxyphosphonates by the kinetic resolution (KR) of between the oxygen in the phosphorus–oxygen double bond of
racemic a-hydroxyphosphonates have been developed.2 Recently, phosphonic acid derivatives and intermediate I should be
Onomura reported the KR of racemic a-hydroxyphosphonates using observed during asymmetric esterification and (ii) this strategy
an organometallic species;3 however, to the best of our knowledge, could be applied to the KR of racemic a-hydroxyphosphonates
organocatalytic methods for the KR of racemic a-hydroxy- similar to that of racemic a-hydroxycarboxylates.
phosphonates have not been described to date. Thus, we planned
Herein, we report a novel and practical KR of racemic
to develop an effective route for the preparation of various a-hydroxyphosphonates using free carboxylic acids. The reaction
chiral a-hydroxyphosphonates via the KR of racemic a-hydroxy- proceeds with the promotion of pivalic anhydride using a chiral
phosphonates using an organocatalyst.
acyl-transfer catalyst and is an application of our MA formation
In 2007, we reported the first asymmetric esterification4a of technology for enantioselective esterification.
free carboxylic acids with racemic secondary benzylic alcohols in the
presence of carboxylic anhydrides as coupling reagents and optically phenylpropylphosphonate ((Æ)-1) using diphenylacetic acid in
active acyl-transfer catalysts, such as (S)-tetramisole and (R)-benzo-
tetramisole ((R)-BTM), which were popularized by Birman et al.5
Originally, Birman and coworkers employed propanoic anhydride or
isobutyric anhydride as an acyl donor for the enantioselective
acylation of racemic secondary alcohols, and several other
groups have subsequently explored the use of symmetric
anhydrides for the KR of racemic compounds with additional
variations of the acyl-transfer catalysts.6 We also achieved the KR
of racemic 2-hyroxyalkanoates4b and 2-hydroxylactones4c using
First, we examined the KR of racemic dimethyl 1-hydroxy-3-
Department of Applied Chemisty, Faculty of Science, Tokyo University of Science,
1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan.
Fig. 1 Calculated transition structures (ts-(R) and ts-(S)) required to form the
corresponding esters, starting from methyl (R)-lactate and methyl (S)-lactate with
the ion pair intermediate I.
E-mail: shiina@rs.kagu.tus.ac.jp; Fax: +81 3 3260 5609; Tel: +81 3 3260 4271
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc44293d
c
10700 Chem. Commun., 2013, 49, 10700--10702
This journal is The Royal Society of Chemistry 2013

View Article Online
Communication
ChemComm
Table 3 Kinetic resolution of racemic 1-hydroxy-3-phenylpropylphosphonates
(Æ)-1, 3, and 5
the presence of pivalic anhydride and (R)-BTM in diethyl ether
at room temperature for 12 h, which were former optimized
conditions for 2-hydroxyalkanoates.4b The reaction proceeded
smoothly to afford the corresponding chiral diphenylacetate
((S)-2a; 46% yield, 98% ee) and the recovered alcohol ((R)-1;
52% yield, 88% ee, s = 266). Fortunately, the desired chiral ester
(S)-2a was also obtained with an extremely high enantiopurity
and s-value8 when THF was used as the solvent (46% yield,
99% ee, s = 419).
Entry
R
Ester yield/% (ee/%) Alcohol yield/% (ee/%)
s
1
2
3
Me (1) 46 (99)
53 (89)
52 (87)
50 (93)
419
337
106
Et (3)
46 (98)
47 (94)
Next, we investigated the scope of the reaction in THF with
respect to the carboxylic acid (Table 1). The use of acetic acid
afforded the corresponding acetate (S)-2b in good yield and
Ph (5)
selectivity (entry 1; 45% yield, 95% ee, s = 88). The KR using respectively).9 Based on these results, it was revealed that the
propanoic acid, 3-phenylpropanoic acid, isobutyric acid, and MA method using diphenylacetic acid with pivalic anhydride is the
cyclohexanecarboxylic acid (entries 2–5) yielded (S)-2c–2f, most suitable protocol to provide the desired chiral (S)-ester and
respectively, also with good selectivities (s = 110, 96, 286, and the recovered chiral (R)-alcohol with high enantioselectivities.
96, respectively). Diphenylacetic acid was found to be the
We further examined the effect of changing the substituents
preferred carboxylic acid for the enantioselective esterification in the phosphonate moiety of the 1-hydroxy-3-phenylpropyl-
of (Æ)-1 to provide the corresponding chiral a-acyloxyphosphonate phosphonates reacting with diphenylacetic acid (Table 3). The
and a-hydroxyphosphonate (entry 6; s = 419).
asymmetric esterification of diethyl 1-hydroxy-3-phenylpropyl-
We have demonstrated additional experiments using symmetric phosphonate ((Æ)-3) rapidly occurred to afford the corres-
anhydrides (SAs) for drawing a comparison between the MA method ponding diphenylacetic acid ester (S)-4 (entry 2; R = Et, 46%
and the SA method (Table 2). In entries 1 and 2, the average s-values yield, 98% ee) and the recovered alcohol (R)-3 (52% yield,
(for two runs) of the KR of (Æ)-1 using diphenylacetic acid and 87% ee) with an excellent s-value (s = 337). The reaction of
isobutyric acid are presented (sav = 427 and 246, respectively).9 On diphenyl 1-hydroxy-3-phenylpropylphosphonate ((Æ)-5) provided
the other hand, we carried out the KR of (Æ)-1 using diphenylacetic nearly the same yield of the ester (S)-6 but with slightly lower
anhydride (DPHAA)10 or isobutyric anhydride,5 and the average enantiomeric excess (entry 3; R = Ph, 47% yield, 94% ee, s = 106).
s-values are also shown in entries 3 and 4 (sav = 362 and 122,
Finally, the esterification of various racemic dimethyl
1-hydroxyphosphonates was examined to assess the generality
of this method. The reactions were performed using
0.75 equivalents of diphenylacetic acid to obtain the recovered
alcohols (R)-7a–k with higher enantiopurity (Table 4). In entry 1,
racemic dimethyl 1-hydroxypropylphosphonate ((Æ)-7a; R = Et)
was successfully resolved to the corresponding ester (S)-8a (51%
yield) and the recovered alcohol (R)-7a (41% yield) with extremely
high enantiomeric excesses (95% ee for (S)-8a, >99% ee for
(R)-7a). When the reaction was carried out using racemic
dimethyl 1-hydroxyalkylphosphonates bearing linear alkyl sub-
stituents R next to the phosphonate group such as (Æ)-7b, 7c,
7g, 7i, and 7k, the recovered alcohols (R)-7b, 7c, 7g, 7i, and 7k
were obtained in good yields with high enantiomeric excesses
(entries 2, 3, 9, 12, and 15; 43–49% yield, >99% ee for all cases).
Using 3-phenylpropanoic acid as a less bulky acyl donor instead
of diphenylacetic acid was very effective for the asymmetric
esterification of the hindered alcohols such as (Æ)-7d (entry 5;
R = i-Pr, 51% yield, 91% ee, s = 74) and (Æ)-7f (entry 8; R = t-Bu,
46% yield, 89% ee, s = 43). Next, the reaction of the substrate
(Æ)-7h (R = TBDPSOCH2) with a b-silyloxy functional group was
investigated, and a fairly good result was obtained when using
0.5 equivalents of diphenylacetic acid (entry 11; s = 463).
Although the reaction of the b-amino-functionalized substrate
(Æ)-7j (R = BocNHCH2) with 0.75 equivalents of diphenylacetic
acid gave the desired a-acyloxyphosphonates (S)-8j in over 50%
yield but with unsatisfactory selectivity (entry 13; 55% yield,
73% ee), as with (Æ)-7h, the use of 0.5 equivalents of diphenyl-
acetic acid improved the enantiopurity of the product (S)-8j
(entry 14; 50% yield, 85% ee). We further found that the KR of
Table 1 Kinetic resolution of racemic 1-hydroxy-3-phenylpropylphosphonate
((Æ)-1) with a variety of carboxylic acids
Entry
R
Ester yield/% (ee/%) Alcohol yield/% (ee/%) s
1
2
3
4
5
6
Me (b)
Et (c)
Ph(CH2)2 (d) 48 (94)
i-Pr (e)
c-Hex (f)
Ph2CH (a)
45 (95)
49 (95)
55 (78)
51 (89)
50 (90)
51 (87)
54 (84)
53 (89)
88
110
96
286
96
419
48 (98)
46 (95)
46 (99)
Table 2 Kinetic resolution of (Æ)-1 using a mixed anhydride (MA) method and a
symmetric anhydride (SA) method
Ester yieldav/% Alcohol yieldav/%
Entry Conditions
R
(eeav/%)
(eeav/%)
sav
1
2
3
4
A [MA]
A [MA]
B [SA]
B [SA]
Ph2CH (a) 46 (99)
54 (86)
54 (80)
55 (78)
59 (70)
427
246
362
122
i-Pr (e) 46 (98)
Ph2CH (a) 44 (99)
i-Pr (e) 40 (97)
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 10700--10702 10701

View Article Online
ChemComm
Communication
Table 4 Kinetic resolution of various dimethyl 1-hydroxyphosphonates (Æ)-7a–k
theoretical calculations clearly show that ts-(R)-7a (for formation
of the (R)-ester) has a higher energy compared with that of
ts-(S)-7a (for formation of the (S)-ester); therefore, the desired
(S)-ester was selectively obtained by the rapid transformation
through the transition state ts-(S)-7a.
In summary, we have developed an efficient method for
preparing chiral a-hydroxyphosphonates in good yields with
high selectivities by the kinetic resolution of the racemic
substrates in the presence of diphenylacetic acid, pivalic anhydride,
and (R)-BTM.
Ester yield/%
(ee/%)
Alcohol yield/%
(ee/%)
Entry
R
s
1
Et (7a)
Ph(CH2)2 (7b)
n-Pr (7c)
i-Pr (7d)
i-Pr
c-Hex (7e)
t-Bu (7f)
t-Bu
51 (95)
48 (98)
53 (94)
27 (95)
51 (91)
43 (98)
4 (96)
46 (89)
49 (95)
50 (91)
46 (99)
52 (94)
55 (73)
50 (85)
53 (87)
41 (>99)
49 (>99)
43 (>99)
67 (28)
47 (93)
52 (76)
96 (3)
47 (83)
46 (>99)
48 (99)
54 (89)
48 (>99)
43 (99)
47 (87)
46 (>99)
225
518
204
51
2a
3
4
5b
6
74
Notes and references
191
53
7
´
1 For a-hydroxyphosphonates: (a) A. Szymanska, M. Szymczak, J. Boryski,
8b
9
43
´
J. Stawinski, A. Kraszewski, G. Collu, G. Sanna, G. Giliberti, R. Loddo
Bn (7g)
243
112
463
203
30
and P. La Colla, Bioorg. Med. Chem., 2006, 14, 1924; (b) J. J. Hale,
W. Neway, S. G. Mills, R. Hajdu, C. A. Keohane, M. Rosenbach,
J. Milligan, G.-J. Shei, G. Chrebet, J. Bergstrom, D. Card, G. C. Koo,
S. L. Koprak, J. J. Jackson, H. Rosen and S. Mandala, Bioorg. Med. Chem.
10
11c
12
13
14c
15
TBDPSOCH2 (7h)
TBDPSOCH2
BnO(CH2)2 (7i)
BocNHCH2 (7j)
BocNHCH2
CbzNH(CH2)2 (7k)
´
Lett., 2004, 14, 3351; (c) P. Nguyen-Ba, N. Turcotte, L. Yuen, J. Bedard,
33
84
`
M. Quimpere and L. Chan, Bioorg. Med. Chem. Lett., 1998, 8, 3561;
(d) T.-H. Chan, Y.-C. Xin and M. von Itzstein, J. Org. Chem., 1997,
62, 3500; (e) J. Heilmann and W. F. Maier, Angew. Chem., Int. Ed. Engl.,
1994, 33, 471; ( f ) T. R. Burke Jr., Z.-H. Li, J. B. Bolen and V. E. Marquez,
J. Med. Chem., 1991, 34, 1577. For peptide analogues: (g) D. V. Patel,
K. Rielly-Gauvin, D. E. Ryono, C. A. Free, W. Lynn Rogers, S. A. Smith,
J. M. DeForrest, R. S. Oehl and E. W. Petrillo Jr., J. Med. Chem., 1995,
38, 4557; (h) B. Stowasser, K.-H. Budt, L. Jian-Qi, A. Peyman and
D. Ruppert, Tetrahedron Lett., 1992, 33, 6625; (i) D. V. Patel, K. Rielly-
Gauvin and D. E. Ryono, Tetrahedron Lett., 1990, 31, 5591;
( j) D. V. Patel, K. Rielly-Gauvin and D. E. Ryono, Tetrahedron Lett.,
1990, 31, 5587. For a-amino phosphonates: (k) R. Hirschmann,
A. B. Smith III, C. M. Taylor, P. A. Benkovic, S. D. Taylor,
K. M. Yager, P. A. Sprengeler and S. J. Benkovic, Science, 1994,
265, 234; (l) P. P. Giannousis and P. A. Bartlett, J. Med. Chem., 1987,
30, 1603.
a
b
7b = 1, 8b = 2a. Reaction conditions: 0.75 eq. of Ph(CH2)2COOH was
used instead of Ph2CHCOOH, and the corresponding 3-phenylpropano-
ates (9d and 9f) were obtained instead of diphenylacetates (8d and 8f).
c
Reaction conditions: 0.5 eq. of Ph2CHCOOH, 0.6 eq. of Piv2O, 1.2 eq.
of i-Pr2NEt.
2 (a) Y. Zhang, C. Yuan and Z. Li, Tetrahedron, 2002, 58, 2973;
`
¨
(b) O. Pamies and J.-E. Backvall, J. Org. Chem., 2003, 68, 4815;
(c) K. Wang, Y. Zhang and C. Yuan, Org. Biomol. Chem., 2003,
1, 3564; (d) A. Woschek, W. Lindner and F. Hammerschmidt, Adv.
Synth. Catal., 2003, 345, 1287.
3 Y. Demizu, A. Moriyama and O. Onomura, Tetrahedron Lett., 2009,
50, 5241.
4 (a) I. Shiina and K. Nakata, Tetrahedron Lett., 2007, 48, 8314;
(b) I. Shiina, K. Nakata, K. Ono, M. Sugimoto and A. Sekiguchi,
Chem.–Eur. J., 2010, 16, 167; (c) K. Nakata, K. Gotoh, K. Ono,
K. Futami and I. Shiina, Org. Lett., 2013, 15, 1170.
5 (a) V. B. Birman and X. Li, Org. Lett., 2006, 8, 1351; (b) V. B. Birman
and L. Guo, Org. Lett., 2006, 8, 4859; (c) X. Li, H. Jiang, E. W. Uffman,
L. Guo, Y. Zhang, X. Yang and V. B. Birman, J. Org. Chem., 2012,
77, 1722.
6 (a) H. Zhou, Q. Xu and P. Chen, Tetrahedron, 2008, 64, 6494;
(b) Q. Xu, H. Zhou, X. Geng and P. Chen, Tetrahedron, 2009,
65, 2232; (c) P. Chen, Y. Zhang, H. Zhou and Q. Xu, Acta Chim.
Sin., 2010, 68, 1431; (d) B. Hu, M. Meng, Z. Wang, W. Du, J. S. Fossey,
X. Hu and W.-P. Deng, J. Am. Chem. Soc., 2010, 132, 17041; (e) B. Hu,
M. Meng, J. S. Fossey, W. Mo, X. Hu and W.-P. Deng, Chem.
Commun., 2011, 47, 10632; ( f ) D. Belmessieri, C. Joannesse,
P. A. Woods, C. MacGregor, C. Jones, C. D. Campbell,
Fig. 2 Calculated transition structures (ts-(S)-7a and ts-(R)-7a) derived from
intermediate I and (S)-7a or (R)-7a.
the g-amino-functionalized substrate (Æ)-7k (R = CbzNH(CH2)2)
with 0.75 equivalents of diphenylacetic acid afforded the
desired a-acyloxyphosphonate (S)-8k with good enantiomeric
excess (entry 15; 53% yield, 87% ee) along with the recovered
enantiomerically pure alcohol (R)-7k (46% yield, >99% ee).
Determination of the transition states involved in the for-
mation of the chiral (S)-ester from dimethyl (S)-1-hydroxypro-
pylphosphonate ((S)-7a) with intermediate I was carried out
using DFT calculations at the B3LYP/6-31G*//B3LYP/6-31G*
level of theory, as previously reported for the KR of 2-hydroxy-
alkanoates.4b Among the several calculated transition states,
the most stable structure (ts-(S)-7a) is depicted in Fig. 2. The
´
C. P. Johnston, N. Duguet, C. Concellon, R. A. Bragg and
A. D. Smith, Org. Biomol. Chem., 2011, 9, 559. See also;
(g) M. Kobayashi and S. Okamoto, Tetrahedron Lett., 2006, 47, 4347.
7 DFT study of the DMAP-catalyzed acetylation: (a) S. Xu, I. Held,
B. Kempf, H. Mayr, W. Steglich and H. Zipse, Chem.–Eur. J., 2005,
11, 4751. The origin of the enantioselectivity in the CF3–PIP-cata-
lyzed KR was also discussed by using DFT calculations: (b) X. Li,
P. Liu, K. N. Houk and V. B. Birman, J. Am. Chem. Soc., 2008,
130, 13836.
8 H. B. Kagan and J. C. Fiaud, Top. Stereochem., 1988, 18, 249.
9 All experimental data were provided in ESI†.
10 K. Nakata, A. Sekiguchi and I. Shiina, Tetrahedron: Asymmetry, 2011,
22, 1610.
c
10702 Chem. Commun., 2013, 49, 10700--10702
This journal is The Royal Society of Chemistry 2013