Unusual regioselection in the Mitsunobu reactions of syn-2,3-dihydroxy esters: Synthesis of statine and its diastereomer

Article abstract of DOI:10.1021/jo015967f

Mitsunobu reactions of syn-2,3-dihydroxy esters exhibit a complete regioselection for the β-hydroxyl group. Benzoylation, azidation, and tosylation have been performed under these conditions. β-Functionalizations of syn-2,3-dihydroxy esters are uncommon, and the Mitsunobu reactions are complementary to other diol chemistries in the regioselection. In addition, the configurational inversion accompanying the Mitsunobu protocol offers a means for diastereochemical diversity, as exemplified by a synthesis of statine and its anti diastereomer. These findings will further expand the synthetic utilities of the Sharpless AD process.

Full text of DOI:10.1021/jo015967f

J . Org. Chem. 2002, 67, 2689-2691
2689
of them gets selectively displaced by nucleophiles. The
regiodifferentiation takes place in the SN2 step, wherein
the adjacent ester group favors the reaction at the C-2
to produce, once again, anti-R-Nu-â-hydroxy ester-type
compounds. The cyclic activating groups studied in this
approach include cyclic sulfates,5 sulfites,6 carbonates,7
and thionocarbonates8 as well as cyclic acetoxonium ions.9
The cyclic thionocarbonates8 and more recent cyclic
iminocarbonates10 are unique in that they can undergo
rearrangements to protected hydroxy thiol and amino
alcohol functionalities, respectively, with net retention
of configurations at both carbinol carbons. The sulfur or
nitrogen in these rearrangements is still directed at C-2
to produce, after suitable deprotections, syn-R-sufhydryl
(or amino)-â-hydroxy esters.11
This leaves the â-hydroxyl-selective functionalizations
of syn-2,3-dihydroxy esters a very much undeveloped
area. A rare case of â-hydroxyl-selective acylation has
been reported in acidic hydrolysis of the cyclic ortho
esters.12
In addition to the regioselection, the inability of the
AD process to produce anti diols means that the question
of diastereochemical diversity (syn/anti) is always an
important issue in this field.13
We postulated that while the electron-withdrawing
inductive effect of the ester group made the R-hydroxyl
group more acidic in 2,3-dihydroxy esters, the same effect
would make the nonbonding electrons of the â-hydroxyl
oxygen more nucleophilic. Therefore, under suitable
reaction conditions in which the hydroxyls are not even
partially deprotonated, electrophiles would react selec-
tively with the â-hydroxyl group. A similar case of
unequal nucleophilicities is well-known in amino acid
chemistry where R-amino groups are far less reactive
than ω-amino groups.14 Of the various alcohol chemistries
usually performed under nonbasic reaction conditions,
Mitsunobu reactions seemed paticularly interesting to
investigate as they would offer a means of addressing
not only regiodiversity but also diastereodiversity issues
as well (vide infra).15
Un u su a l Regioselection in th e Mitsu n obu
Rea ction s of syn -2,3-Dih yd r oxy Ester s:
Syn th esis of Sta tin e a n d Its Dia ster eom er
Soo Y. Ko
Department of Chemistry and Division of Molecular and
Life Sciences, Ewha Womans University,
Seoul 120-750, Korea
sooyko@mm.ewha.ac.kr
Received J uly 27, 2001
Abstr a ct: Mitsunobu reactions of syn-2,3-dihydroxy esters
exhibit a complete regioselection for the â-hydroxyl group.
Benzoylation, azidation, and tosylation have been performed
under these conditions. â-Functionalizations of syn-2,3-
dihydroxy esters are uncommon, and the Mitsunobu reac-
tions are complementary to other diol chemistries in the
regioselection. In addition, the configurational inversion
accompanying the Mitsunobu protocol offers a means for
diastereochemical diversity, as exemplified by a synthesis
of statine and its anti diastereomer. These findings will
further expand the synthetic utilities of the Sharpless AD
process.
The advent of the Sharpless asymmetric dihydroxyla-
tion (AD) process has provided easy access to enantiopure
vicinal-diols.1 Selective transformations of diols further
expand the synthetic utilities of the AD. Their discover-
ies, therefore, are much sought after. Of various AD
products, syn-2,3-dihydroxy esters are the most common,
perhaps because reliable methods exist for the construc-
tion of the substrates, (E)-R,â-unsaturated esters, with
their geometry being well established.2 As for selective
transformations of AD products, syn-2,3-dihydroxy esters
again provide a fertile ground as the presence of the ester
group renders some of the alcohol chemistry regioselec-
tive.
Most of the previous works in this area result in
regioselective reactions at the R-hydroxyl group of syn-
2,3-dihydroxy esters, employing one of the following two
strategies. One approach takes advantage of the higher
acidity of the R-hydroxyl group (induced by the adjacent
ester group).3 Under basic reaction conditions, the more
acidic R-hydroxyl group gets selectively deprotonated
(if only partially), and the resulting R-alkoxide (or
R-Oδ-‚‚‚‚Hδ+) regioselectively reacts with electrophiles.
Sulfonylations (RSO2Cl with pyridine or Et3N) have been
reported to produce a complete regioselection for the
R-hydroxyl group. The monosulfonates thus produced are
useful intermediates for synthesis of various compounds
with the general structure of anti-R-Nu-â-hydroxy esters.4
In the second approach, both hydroxyls are activated,
usually in the form of cyclic intermediates; then, only one
Using the crotonate ester diol 1 as a model substrate
devoid of any strong steric bias, we performed Mitsunobu
reactions with triphenylphosphine-DEAD in the presence
(5) (a) Gao, Y.; Sharpless, K. B. J . Am. Chem. Soc. 1988, 110, 7538.
(b) Lohray, B. B. Synthesis 1992, 1035. (c) Byun, H. S.; He, L.; Bittman,
R. Tetrahedron 2000, 56, 7051.
(6) (a) Gao, Y.; Zepp, C. M. Tetrahedron Lett. 1991, 32, 3155.
(7) (a) Kang, S. K.; Park, H. S.; Rho, H. S.; Yoon, S. H.; Shin, J . S.
J . Chem. Soc., Perkin Trans. 1 1994, 3513. (b) Chang, H.-T.; Sharpless,
K. B. Tetrahedron Lett. 1996, 37, 3219.
(8) Ko, S. Y. J . Org. Chem. 1995, 60, 6250.
(9) (a) Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515.
(b) Golding, B. T.; Hall, D. R.; Sakriker, S. J . Chem. Soc., Perkin Trans.
1 1973, 1214.
(10) Cho, G. Y.; Ko, S. Y. J . Org. Chem. 1999, 64, 8745.
(11) cf.: (a) Cho, G. Y.; Park, J . N.; Ko, S. Y. Tetrahedron Lett. 2000,
41, 1789. (b) Park, J . N.; Ko, S. Y.; Koh, H. Y. Tetrahedron Lett. 2000,
41, 5553. (c) Cho, G. Y.; An, K. M.; Ko, S. Y. Bull. Korean Chem. Soc.
2001, 22, 432.
(12) Oikawa, M.; Wada, A.; Okazaki, F.; Kusumoto, S. J . Org. Chem.
1996, 61, 4469.
(13) cf.: (a) Wang, L.; Sharpless, K. B. J . Am. Chem. Soc. 1992, 114,
7568. (b) Ko, S. Y.; Malik, M.; Dickinson, A. F. J . Org. Chem. 1994,
59, 2570.
(14) Bodanszky, M. Principles of Peptide Synthesis; Springer-Ver-
lag: Berlin, 1984.
(15) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Hughes, D. L. Organic
Reactions; J ohn Wiley & Sons: New York, 1992; Vol. 42, pp 235-657.
(1) Review: Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483.
(2) (a) Wadsworth, W. S. Org. React. 1992, 25, 73. (b) Beatmann,
H. J .; Vostrowsky, O. Top. Curr. Chem. 1983, 109, 85.
(3) Fleming, P. R.; Sharpless, K. B. J . Org. Chem. 1991, 56, 2869.
(4) (a) Hoffman, R. V. Tetrahedron 1991, 47, 1109. (b) Hoffman, R.
V.; Kim, H. O. Tetrahedron 1992, 48, 3007. (c) Rao, A. V. R.; Rao, S.
P.; Bhanu, M. N. J . Chem. Soc., Chem. Commun. 1992, 859.
10.1021/jo015967f CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/22/2002

2690 J . Org. Chem., Vol. 67, No. 8, 2002
Notes
Sch em e 1
Ta ble 1.
Acrylate diol 4 proved to be no exception in â-hydroxyl-
selective Mitsunobu benzoylation (entry 6). This last
example is an interesting case and points to the impor-
tance of electronic factors in the regioselective Mitsunobu
reactions of 2,3-dihydroxy esters.19
When alkyl- or aryl-substituted glycols such as propy-
lene diol or styrene diol are subjected to Mitsunobu
conditions, the reactions are reported to take place
entry
R
H-Nu
R:âa
yieldb
1
2
3
4
5
6
Me(1)
Me(1)
Me(1)
Ph(2)
PhCO2H
HN3
Pyr‚HOTs
HN3
HN3
PhCO2H
â only
â only
â only
â only
â only
â only
57%
78%
55%
82%
67%c
88%
selectively at the more substituted carbinol carbon.19
A
cyclic intermediate has been proposed for these reactions
wherein steric effects are thought to determine the
regiochemical outcomes. The results with acrylate diol
(entry 6), on the other hand, suggest that the electronic
effects overshadow the steric ones in Mitsunobu reactions
of carboxyl-substituted glycol substrates. A model study
shows that a cyclic intermediate may not necessarily be
involved in these regioselective Mitsunobu reactions of
2,3-dihydroxy esters.20
p-MeO-Ph(3)
H(4)d
a
Determined by NMR spectroscopy of the crude product.
b
Isolated yields of the â-regioisomers. Unreacted starting materi-
als and some â-elimination products (for entries 1 and 3) make
up the rest. c A mixture of diastereomers (anti:syn )3:1, both
d
â-regioisomers) was obtained. Butyl ester was used.
In addition to the unique regioselection, Mitsunobu
reactions of 2,3-dihydroxy esters also provide a means
of realizing diastereochemical diversity (syn/anti), as
demonstrated in the following synthesis of statine and
its anti diastereomer (Scheme 1).21 The key steps include
the AD of an appropriate (E)-R,â-unsaturated ester
followed either by â-regioselective Mitsunobu azidation
(for the anti diastereomer) or by â-regioselective Mit-
sunobu tosylation and a subsequent substitution of an
amino function (for the natural syn-statine).
of benzoic acid, HN3,16 or pyridinium tosylate as the
nucleophile (entries 1-3, Table 1). The reactions took
place at the â-hydroxyl group with a complete regio-
selection, as judged by NMR spectroscopy of the crude
products.17 In cases of benzoylation and tosylation, some
â-eliminations accompanied the regioselective Mitsunobu
reactions, resulting in lower yields of the desired â-ben-
zoate or â-tosylate. In no case, however, were the
R-substitution products observed.17 Cinnamate ester diol
2 and its p-methoxy analogue 3 also showed a complete
regioselection for the â-hydroxyl group when reacted with
HN3 under Mitsunobu conditions (entries 4 and 518).
The required substrate (5) for the AD was constructed
with a high selectivity (E:Z ) 98:2) via a Horner-
Emmons reaction. The AD of the (E)-isomer 5 (using AD-
(16) Loibner, H.; Zbral, E. Helv. Chim. Acta 1976, 59, 2000.
(17) Some of the R-regioisomeric products (anti-R-azido-â-hydroxyl
and anti-R-benzoyloxy-â-hydroxyl compounds) and the syn diastereo-
mers (R- or â-monotosylates, R- or â-monobenzoates, and â-azide) were
separately prepared (see refs 8 and 9a), and their absence in the crude
Mitsunobu reaction product was vigorously established.
(18) See Table 1, footnote c.
(19) (a) Pautard, A. M.; Evans, S. A., J r. J . Org. Chem. 1988, 53,
2300. (b) Pautard-Cooper, A.; Evans, S. A., J r. J . Org. Chem. 1989,
54, 2485.
(20) See Supporting Information for details.

Notes
J . Org. Chem., Vol. 67, No. 8, 2002 2691
mix-R) yielded the (2R,3S)-syn-2,3-dihydroxy ester 6 in
96% yield and 99% ee.22 Mitsunobu azidation (TPP,
DEAD, HN3) provided the anti-R-hydroxy-â-azido ester
8b in 82% yield. The synthesis of the corresponding syn
diastereomer required two steps: Mitsunobu tosylation
(TPP, DEAD, TPPS) to give anti-R-hydroxy-â-tosylate
ester 7 in 70% yield, followed by a displacement of the
â-tosylate by azide to give syn-R-hydroxy-â-azido ester
8a in 90% yield. The subsequent transformations ran in
parallel for each diastereomer. The R-hydroxyl group was
TBDMS-protected (9) and the ester function hydrolyzed
(10). The required one-carbon extension was achieved via
Arndt-Eistert reaction to give 12.23 Desilylation followed
by azide reduction yielded natural syn-statine (14a ) and
its anti diastereomer (14b) in parallel.
type compounds (Nu ) OBz, OTs, N3). In addition,
Mitsunobu tosylation products (anti-â-tosylates) can be
converted to various syn-R-hydroxy-â-Nu ester-type com-
pounds. Thus, the Mitsunobu protocol allows not only a
unique â-hydroxyl regioselection but also syn/anti dia-
stereochemical diversity with syn-2,3-dihydroxy ester
substrates. With these additions to the repertoire, the
synthetic utilities of the AD process will be further
expanded.
Exp er im en ta l Section
Gen er a l P r oced u r e for Regioselective Mitsu n obu Rea c-
tion s of syn -2,3-Dih yd r oxy Ester s. The syn-2,3-dihydroxy
ester substrate was dissolved in THF (4 mL/mmol diol), and the
solution was cooled in an ice bath. Triphenylphosphine (1.2
equiv) and H-Nu (2 equiv) were added. DEAD (1.3 equiv) was
added dropwise as a THF solution (2 mL). The mixture was
warmed to room temperature and stirred. When the reaction
was judged to be complete (TLC), the mixture was partitioned
between ethyl acetate and 10% NaHCO3 aqueous solution. The
aqueous phase was extracted with portions of ethyl acetate. The
combined organic phases were washed with brine and dried with
Na2SO4. Following filtration and concentration, the crude prod-
uct was first analyzed by NMR for the regioselectivity. It was
then purified by flash silica column chromatography.
In conclusion, Mitsunobu reactions of syn-2,3-dihy-
droxy esters exhibit a complete regioselection for the
â-hydroxyl group to give the anti-R-hydroxy-â-Nu ester-
(21) For recent syntheses, see: (a) Alemany, C.; Bach, J .; Farras,
J .; Garcia, J . Org. Lett. 1999, 1, 1831. (b) Sengupta, S.; Sensarma, D.
Tetrahedron: Asymmetry 1999, 10, 4633. (c) Bonin, B. F.; Franchini,
C. M.; Fochi, M.; Laboroi, F.; Mazzanti, G.; Ricci, A.; Varchi, G. J . Org.
Chem. 1999, 64, 8008. (d) Hoffman, R. V.; Tao, J . J . Org. Chem. 1997,
62, 2292. (e) Reddy, G. V.; Rao, G. V.; Lyenga, D. S. Tetrahedron Lett.
1999, 40, 775. (f) Veeresha, G.; Datta, A. Tetrahedron Lett. 1997, 38,
5223. (g) Bravo, P.; Corradi, E.; Pesenti, C.; Vergani, B.; Viani, F.;
Volonterio, A.; Zanda, M. Tetrahedron: Asymmetry 1998, 9, 3731. (h)
Meunier, N.; Veith, U.; J ager, V. Chem. Commun. 1996, 331. (i) Ender,
D.; Reinhold, U. Angew. Chem., Int. Ed. Engl. 1995, 34, 1219. (j)
Neibois, P.; Greene, A. E. J . Org. Chem. 1996, 61, 5210. (k) Gennari,
C.; Pain, G.; Moresca, D. J . Org. Chem. 1995, 60, 6248.
(22) The optical purity was determined using chiral HPLC (Pirkle
column).
(23) (a) Godemann, K.; Ernest, M.; Hoyer, D.; Seebach, D. Angew.
Chem., Int. Ed. 1999, 38, 1223. (b) Seebach, D.; Overhand, M.;
Kunhnle, N. M.; Martinoni, B. Helv. Chim. Acta 1996, 79, 913. (c)
Podlech, J .; Seebach, D. Liebigs Ann. 1995, 1217.
Ack n ow led gm en t. This work was supported by the
MOST (00-B-WB-06-A-07).
Su p p or tin g In for m a tion Ava ila ble: The model study,20
experimental procedure, and spectral data for the synthetic
intermediates described in the paper. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
J O015967F