Stereoselective Carbon-Carbon Bond Formation via the Mitsunobu Displacement of Chiral Secondary Benzylic Alcohols

Article abstract of DOI:10.1021/ol036380l

(Matrix presented) The stereoselective displacement of a variety of chiral benzylic alcohols with triethylmethanetricarboxylate (TEMT) under Mitsunobu conditions (DEAD, PMe₃) has been demonstrated to proceed in good yield (70-94%) and with a high degree of inversion. Subsequent saponification and decarboxylation of the products thus obtained provide chiral 3-aryl-3-substituted propanoic acids without racemization.

Full text of DOI:10.1021/ol036380l

ORGANIC
LETTERS
2004
Vol. 6, No. 4
573-576
Stereoselective Carbon−Carbon Bond
Formation via the Mitsunobu
Displacement of Chiral Secondary
Benzylic Alcohols
Michael C. Hillier,* Jean-Nicolas Desrosiers, Jean-Franc¸ois Marcoux, and
Edward J. J. Grabowski
Department of Process Research, Merck & Co., Inc., P.O. Box 2000,
Rahway, New Jersey 07065
michael_hillier@merck.com
Received December 5, 2003
ABSTRACT
The stereoselective displacement of a variety of chiral benzylic alcohols with triethylmethanetricarboxylate (TEMT) under Mitsunobu conditions
(DEAD, PMe3) has been demonstrated to proceed in good yield (70−94%) and with a high degree of inversion. Subsequent saponification and
decarboxylation of the products thus obtained provide chiral 3-aryl-3-substituted propanoic acids without racemization.
There are a number of practical methods for the stereose-
lective synthesis of 3,3-disubstituted propanoic acids (Figure
1). The 1,4-addition of organometallics into chiral R,â-
unsaturated esters and amides, for example, has been
demonstrated to provide product in high chemical and
diastereomeric purity.1,2 This same reaction has been ac-
complished in an enantioselective fashion with a variety of
nucleophiles and chiral catalysts or promoters.3,4 Alterna-
tively, the asymmetric hydrogenation5 of prochiral 3,3-
substituted propenoic acids is an effective method for the
construction of these moieties. In light of the general
occurrence of this class of compounds, we became interested
in alternative routes to these intermediates. Specifically, we
were intrigued by the idea of a direct SN2 displacement of
an activated chiral alcohol with an enolate equivalent to form
a carbon-carbon bond (Figure 1) with inversion of the
carbinol stereocenter.
A survey of the literature revealed relatively few methods
for the displacement of activated alcohols by carbon nucleo-
philes in stereoselective fashion. In one case, Reed and co-
workers have shown that chiral alcohols derived from cyclic
sugars can be displaced with diethyl malonate in high
diastereoselectivity after activation with TMSOTf.6 Research-
ers from Pfizer have demonstrated that a chiral benzylic
mesylate can undergo inversion when treated with a higher
(1) Rossiter, B. E.; Swingle, N. M. Chem. ReV. 1992, 92, 771-806.
(2) (a) Song, Z. J.; Zhao, M.; Desmond, R.; Devine, P.; Tschaen, D. M.;
Tillyer, R.; Frey, L.; Heid, R.; Xu, F.; Foster, B.; Li, J.; Reamer, R.; Volante,
R.; Grabowski, E. J. J.; Dolling, U. H.; Reider, P. J. Okada, S. O.; Kato,
Y.; Mano, E. J. Org. Chem. 1999, 64, 9658-9667. (b) Song, Z. J.; Zhao,
M.; Frey, L.; Li, J.; Tan, L.; Chen, C. Y.; Tschaen, D. M.; Tillyer, R.;
Grabowski, E. J. J.; Volante, R.; Reider, P. J.; Kato, Y.; Okada, S.; Nemoto,
T.; Sato, H.; Akao, A.; Mase, T. Org. Lett. 2001, 3, 3357-3360. (c) Kato,
Y.; Niiyama, K.; Nemoto, T.; Jona, H.; Akao, A.; Okada, S.; Song, Z. J.;
Zhao, M.; Tsuchiya, Y.; Tomimoto, K.; Mase, T. Tetrahedron 2002, 58,
3409-3415.
(3) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033-8061.
(4) (a) Fagnou, K.; Lautens, M. Chem. ReV. 2003, 103, 169-196. (b)
Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829-2844.
(5) (a) Menges, F.; Pfaltz, A. AdV. Synth. Catal. 2002, 344, 40-44. (b)
Tang, W.; Wang, W.; Zhang, X. Angew. Chem., Int. Ed. 2003, 42, 943-
946. (c) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029-3070.
Figure 1. Approaches to 3-aryl-3-substituted propanoic acids.
10.1021/ol036380l CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/16/2004

order phenyl cuprate to provide product in good yield and
with moderate (ca. 4-10%) loss in enantiomeric purity.7
Another interesting and often exploited approach involves
various modifications of the Mitsunobu reaction.8 In 1972,
Mitsunobu and co-workers showed that (R)-2-octanol could
be displaced with ethyl cyanoacetate using triphenylphos-
phine (PPh3) and diethylazodicarboxylate (DEAD), though
product was isolated in low yield and with poor enantiomeric
purity.9 Much additional work has been carried out since
involving low pKa carbon acids and/or specialized activating
reagents with a variety of substrates, both racemic10 and
chiral.11 One particularly interesting example was established
by Palmisano and Cravotto wherein triethylmethanetricar-
boxylate (TEMT), PPh3, and DEAD were used to displace
a diverse array of racemic aliphatic and benzylic alcohols.12
A single chiral substrate was investigated in this work where-
in (S)-ethyl lactate was subjected to SN2-displacement to give
product in moderate yield and good enantioselectivity (87%
ee).13 Due to the simplicity of the reaction conditions and
ease with which the triester products undergo decarboxyla-
tion,10b,f we wanted to examine this reaction in more detail
with other chiral substrates.
Table 1. Optimization of the Mitsunobu Displacement
entry
T, °C
nucl equiv
PR3
solvent
yield, %
1
2
3
4
5
6
7
8
9
0 to rt
0 to rt
rt
rt
rt
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78 to rt
1.5
2
2
2
2
2
2
2
2
PPh3 Et2O
PPh3 Et2O
PPh3 toluene
PCy3 toluene
PBu3 toluene
PBu3 toluene
42
40
12
0
70
72
73
85
75
49
PEt3
toluene
PMe3 toluene/THF
PMe3 THF
PMe3 THF
10
1.5
and 72% yield at -78 °C to rt. A less sterically crowded
phosphine, triethyl phosphine (PEt3), did not enhance
conversion, but trimethyl phosphine (PMe3) was found to
be particularly effective, giving 2 in 85% yield (entry 8) in
a mixture of THF/toluene (1:1) at low temperature. The use
of THF alone led to a slight decrease in yield (75%), and
the conversion suffered (49%) when only 1.5 equiv of the
nucleophile was employed (entry 10).
With a reasonable set of reaction conditions in hand, a
chiral substrate, (R)-R-methyl-2-naphthalenemethanol (3),
was examined to determine the stereoselectivity of this
transformation (Scheme 1). Reaction of the alcohol 3 in THF/
Initially, racemic 2-phenyl ethanol 1 was chosen for
exploration and reaction optimization (Table 1). Using the
original conditions of Palmisano and co-workers, a mixture
of the alcohol 1 (1 equiv), TEMT (1.5-2.0 equiv), and PPh3
(2 equiv) in Et2O at 0 °C was treated with DEAD14 (2 equiv)
followed by warming to room temperature to give the triester
adduct 2 in 40-42% assay yield.15 The use of a less polar
solvent such as toluene was not effective at all, nor was the
replacement of PPh3 with the more bulky tricyclohexylphos-
phine (PCy3). However, when tributylphosphine (PBu3) was
used, product was obtained in 70% yield at room temperature
Scheme 1
(6) Reed, L. A.; Huang, J. T.; McGregor, M.; Goodman, L. Carbohydr.
Res. 1994, 254, 133-140.
(7) Quallich, G. J.; Woodall, T. M. Tetrahedron 1992, 48, 10239-10248.
(8) For a general review of the Mitsunobu reaction, see: Hughes, D. L.
Org. Prep. Proc. Int. 1996, 28, 127-164.
(9) (a) Wada, M.; Mitsunobu, O. Tetrahedron Lett. 1972, 13, 1279-
1282. (b) Kurihara, T.; Suguzaki, M.; Kime, I.; Wada, M.; Mitsunobu, O.
Bull. Chem. Soc. Jpn. 1981, 54, 2107-2112.
(10) (a) Tsunoda, T.; Yamamiya, Y.; Ito, S. Tetrahedron Lett. 1993, 34,
1639-1642. (b) Giovanni, B.; Sisti, M.; Palmisano, G. Tetrahedron:
Asymmetry 1997, 8, 515-518. (c) Shing, T. K. M.; Li, L.-H.; Narkunan,
K. J. Org. Chem. 1997, 62, 1617-1622. (d) Tsunoda, T.; Uemoto, K.;
Ohtani, T.; Kabu, H.; Ito, S. Tetrahedron Lett. 1999, 40, 7359-7362. (e)
Chaturvedi, S.; Otteson, K.; Bergot, J. Tetrahedron Lett. 1999, 40, 8205-
8209. (f) Chaturvedi, S. Patent WO 00/10942. (g) Kim, G. T.; Wenz, M.;
Park, J. I.; Hasserodt, J.; Janda, K. D. Bioorg. Med. Chem. 2002, 10, 1249-
1262. (h) Takacs, J. M.; Xu, Z.; Jiang, X.; Leonov, A. P.; Theriot, G. C.
Org. Lett. 2002, 4, 3843-3845.
(11) (a) Cabaret, D.; Maigrot, N.; Welvart, Z. Tetrahedron Lett. 1981,
22, 5279-5282. (b) Macor, J. E.; Wehner, J. M. Heterocycles 1993, 35,
349-365. (c) Ito, S.; Tsunoda, T. Pure Appl. Chem. 1999, 71, 1053-1057.
(d) Tsunoda, T.; Uemoto, K.; Nagino, C.; Kawamura, M.; Kaku, H.; Ito, S.
Tetrahedron Lett. 1999, 40, 7355-7358. (e) Uemoto, K.; Kawahito, A.;
Matashita, N.; Sakamoto, I.; Kaku, H.; Tsunoda, T. Tetrahedron Lett. 2001,
42, 905-907. (f) Fukumoto, S.; Fukushi, S.; Terao, S.; Shiraishi, M. J.
Chem. Soc., Perkin Trans. 1 1996, 1021-1026.
toluene (1:1) at -78 °C gave the triester adduct 4 in 84%
yield and 93% ee, indicating that a slight amount of
racemization had occurred.16 In THF alone, product was
recovered in significantly lower yield (36%) but in the same
optical purity (93% ee). On the other hand, using toluene as
solvent at -53 °C to rt, 4 was isolated in 88% yield and
96% ee; thus, no loss in optical purity was observed during
the reaction. The displacement could even be carried out at
0 °C in a mixture of toluene:THF (4:1) to give 4 in 96% ee,
(12) Cravotto, G.; Giovenzana, G. B.; Sisti, M.; Palmisano, G. Tetra-
hedron 1996, 52, 13007-13016.
(13) The enantioselectivity of this reaction was determined by deriva-
tization, and comparison of optical rotation to that of a known intermediate.
(14) The activator diisopropylazodicarboxylate (DIAD) was found to be
approximately equivalent in this reaction manifold.
(15) Assay yields were determined via quantitative HPLC analysis by
comparison to a known amount of pure standard.
(16) See the Supporting Information for methods of ee determination.
574
Org. Lett., Vol. 6, No. 4, 2004

Table 2. General Scope of the Methodologya
Table 3. Limitations of the Methodologya
a Conditions: (A) THF/toluene (1:1), -78 °C to rt; (B) toluene, -53
°C to rt.
a Conditions: (A) THF/toluene (1:1), -78 °C to rt; (B) toluene, -53
°C to rt; (C) toluene, 0 °C to rt.
though the conversion was lower (77%). Subsequent saponi-
fication of the triester 4 (96% ee) with NaOH and decar-
boxylation of the resultant tris-acid gave 5 in 81% isolated
yield and with no erosion in enantiomeric purity (96% ee).
Having demonstrated the feasibility of this methodology,
a number of other chiral substrates were examined (Table
2). The enantiomeric excess of the initial triethylester adducts
were not obtained in most cases, rather these intermediates
were carried on to the corresponding 3,3-disubstituted
propanoic acid products.17 For example, starting from (R)-
1-phenylethanol (6a, 99% ee), 8a was isolated in 90% ee
and 61% overall yield after displacement (conditions A),
saponification, and decarboxylation. Using the same three-
step sequence 6b,c gave the corresponding acids 8b,c in
enantiomerically pure form (>99% ee). Cyclic substrates
such as (S)-1-indanol 6f and (R)-1-tetrahydronaphthol 6g also
behaved well under these conditions. On the other hand, the
displacement of sterically hindered substrates was not as
effective. For example, (R)-1-phenyl-1-butanol 6d gave the
triester adduct 7d in a moderate yield (52%) while 6e did
not react at all. However, 7d could be converted to the acid
8d in 55% yield and 95% ee after decarboxylation.18
During these studies, a significant solvent effect was
noticed. For example, the displacement of 6a in toluene at
-53 or 0 °C followed by saponification/decarboxylation gave
the acid 8a in a much improved 99% ee, though in lower
overall yield (49-57%). A similar trend was observed with
indanol (6f) wherein Mitsunobu displacement in toluene gave
7f in 99% ee versus 87% ee in THF/toluene (conditions A).
On the other hand, the inversion of (R)-1-phenyl-1-butanol
6d in toluene led to a much lower yield of the triester adduct
7d (9%), perhaps due to poor substrate solubility.
A number of benzylic, biaryl, and aliphatic alcohol
substrates were also examined using this methodology (Table
3). For example, (S)-1-(4-methoxyphenyl)ethanol 9a gave
(17) In most cases, the triester adducts obtained after alkylation were
very poor substrates for analysis by chiral chromatography methods (i.e.,
SFC, GC, or HPLC).
Org. Lett., Vol. 6, No. 4, 2004
575

of starting material. As such, it is reasonable to assume that
the ionization pathways A or B are stabilized by substrates
with electron donating substituents and that changing solvent
cannot prevent this. Brown20 and van der Gen21 have
observed a similar trend in their study of the Mitsunobu
reaction of p-methoxy substituted benzylic alcohols with
carboxylic acid nucleophiles.
In conclusion, we have demonstrated that the Mitsunobu
reaction is an effective method for the stereoselective
formation of carbon-carbon bonds. The most important
features of this methodology are as follows: (1) the use of
commercially available triethylmethanetricarboxylate (TEMT)
as the carbon acid nucleophile and (2) the use of the trialkyl
phosphine PMe3 along with DEAD to effect the desired
transformation. Neutral or electron-poor substrates can be
alkylated with a high degree of inversion (Table 2), whereas
electron-rich and biaryl systems (9a-c) undergo significant
racemization (Table 3). In some cases, the extent of the
erosion in optical purity can be mitigated through the use of
toluene. Crowded and aliphatic substrates where found not
to be particularly reactive while some benzylic species (9d,e)
led to extensive decomposition. Finally, saponification and
decarboxylation of the alkylated triester intermediates gives
the corresponding acids without loss of enantiomeric purity,
thus representing a viable route to chiral 3-aryl-3-substituted
propanoic acids. We are continuing to explore this reaction
in more complex systems.
Figure 2. Possible modes of racemization.
the acid 11a in 69% overall yield and 60% ee after the three-
step sequence. The electron-rich biaryl alcohol 9b gave the
corresponding triester adduct 10b in 63% isolated yield but
in racemic form. Similarly, 2-methyl-(S)-benzyhydrol 9c
could be converted to the acid 11c in good yield (70%) but
poor enantiomeric purity (40% ee) after the three-step
sequence. However, when toluene was used during the
alkylation step of 9c the ee of 11c increased to 60%.
Commercially available cyanohydrin 9d and 1-phenyl-2-
chloroethanol 9e led to extensive decomposition and did not
give desired product under these conditions.18 Nonbenzylic
and secondary aliphatic substrates 3-pentanol 9f and cyclo-
pentanol 9g reacted in very low yield (<2%).
Clearly, a number of chiral benzylic alcohols (Table 2)
undergo stereoselective Mitsunobu-type displacement with
triethylmethanetricarboxylate in the presence of DEAD and
PMe3. In some cases racemization is observed, in particular
with electron-rich substrates. This erosion in optical purity
Acknowledgment. We thank Mirlinda Biba and Jimmy
Dasilva for the development of chiral assays and Dr. J. Chris
McWilliams for the preparation of 6b,c and 9a.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
might be explained by the generally accepted mechanism
+
for the Mitsunobu reaction, which suggests that ROPR3
I
(Figure 2) is a possible reaction intermediate.19 This species
can ionize via an SN1-type pathway (II, pathway A) prior to
reaction with the nucleophile or may react with THF
(pathway B) to give III as has been proposed by Cabaret
and co-workers.11b The use of toluene seems to dramatically
reduce the amount of racemization in some cases (6a,f and
9c), possibly via destabilization of these ionization pathways.
However, electron-rich substrates such as 9a-c are particu-
larly susceptible, as the corresponding acids 11a-c were
obtained in much lower enantiomeric purity compared to that
OL036380L
(18) Significant amounts of either elimination and/or DEAD incorporation
were observed.
(19) Hughes, D. L.; Reamer, R. A.; Bergan, J. J.; Grabowski, E. J. J. J.
Am. Chem. Soc. 1988, 110, 6487-6491.
(20) (a) Brown, R. F. C.; Jackson, W. R.; McCarthy, T. D. Tetrahedron
Lett. 1993, 34, 1195-1196. (b) Brown, R. F. C.; Jackson, W. R.; McCarthy,
T. D. Tetrahedron 1994, 50, 5469-5488.
(21) Warmerdam, E. G. J. C.; Brussee, J.; Kruse, C. G.; van der Gen,
A. Phosphorous, Sulfur, Silicon 1993, 75, 3-6.
576
Org. Lett., Vol. 6, No. 4, 2004