Asymmetric, organocatalytic, three-step synthesis of γ-hydroxy-(E)- α,β-unsaturated sulfones and esters

Article abstract of DOI:10.1021/ol8020513

(Chemical Equation Presented) Efficient and enantiocontrolled synthesis of γ-hydroxy-α,β-unsaturated sulfones and esters are reported through the reaction of enantioenriched a-selenyl aldehydes with EWG-stabilized carbanions and then a one-pot selenide ox

Full text of DOI:10.1021/ol8020513

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4685-4687
Asymmetric, Organocatalytic, Three-Step
Synthesis of
γ-Hydroxy-(E)-r,ꢀ-Unsaturated Sulfones
and Esters
Kimberly S. Petersen and Gary H. Posner*
Department of Chemistry, Johns Hopkins UniVersity, 3400 Charles Street,
Baltimore, Maryland 21218
ghp@jhu.edu
Received September 2, 2008
ABSTRACT
Efficient and enantiocontrolled synthesis of γ-hydroxy-r,ꢀ-unsaturated sulfones and esters are reported through the reaction of enantioenriched
r-selenyl aldehydes with EWG-stabilized carbanions and then a one-pot selenide oxidation, in situ epoxide formation, and final in situ epoxide
opening.
While studying the metabolites of certain vitamin D3
analogues, we became interested in the synthesis of γ-hy-
droxy-R,ꢀ-unsaturated sulfones and esters. γ-Hydroxy-R,ꢀ-
ethylenic sulfones have previously been used as substrates
in stereocontrolled processes such as conjugate additions and
cycloaddition reactions,1 as substrates for preparation of
enatiomerically pure polypropionate chains or amino alcohol
units,2 and also as intermediates in alkaloid syntheses.3
γ-Hydroxy-R,ꢀ-enoates have been used as sources of R,ꢀ-
epoxyesters, which are highly versatile functionalities and
can be converted into a number of compounds by opening
the oxirane4 and as intermediates in natural product synthe-
ses.5 Use of both of these γ-hydroxy-R,ꢀ-unsaturated systems
as substrates for stereoselective radical reactions has been
explored.6 General methodologies for the asymmetric syn-
thesis of these systems, however, are limited in scope.7 Based
on the utility of such systems in highly stereocontrolled
processes1 and as intermediates in natural product synthe-
ses,3,5 we set out to design a simple, asymmetric general
strategy for their synthesis.
(4) (a) Rodriguez, S.; Vidal, A.; Monroig, J. J.; Gonzalez, F. V.
Tetrahedron Lett. 2004, 45, 5359–5361. (b) Rodriguez, S.; Kneeteman, M.;
Izquierodo, J.; Lopez, I.; Gonzalez, F. V.; Peris, G. Tetrahedron 2006, 62,
11112–11123. (c) Lopez, I.; Rodriguez, S.; Izquierodo, J.; Gonzalez, F. V.
J. Org. Chem. 2007, 72, 6614–6617.
(1) (a) Barton, D. L.; Conrad, P. C.; Fuchs, P. L. Tetrahedron Lett. 1980,
21, 1811–1814. (b) Trost, B. M.; Seoane, P.; Mignani, S.; Acemoglu, M.
J. Am. Chem. Soc. 1989, 111, 7487–7500.
(2) (a) Carretero, J. C.; Dominguez, E. J. Org. Chem. 1993, 58, 1596–
1600. (b) de Blas, J.; Carretero, J. C.; Dominguez, E. Tetrahedron Lett.
1994, 35, 4603–4606. (c) Dominguez, E.; Carretero, J. C. Tetrahedron 1994,
50, 7557–7566.
(5) (a) Jamieson, A. G.; Sutherland, A. Org. Lett. 2007, 9, 1609–1611.
(b) Kotkar, S. P.; Suryavanshi, G. S.; Sudalai, A. Tetrahedron: Asymmetry
2007, 18, 1795–1798. (c) Varseev, G. N.; Maier, M. E. Org. Lett. 2007, 9,
1461–1464. (d) Taber, D. F.; Reddy, P. G.; Arneson, K. O. J. Org. Chem.
2008, 73, 3467–3474.
(3) (a) Rojo, J.; Garcia, M.; Carretero, J. C. Tetrahedron 1993, 49, 9787–
9800. (b) Carretero, J. C.; Arrayas, R. G. J. Org. Chem. 1998, 63, 2993–
3005. (c) de Vincent, J.; Arrayas, R. G.; Canada, J.; Carretero, J. C. Synlett
2000, 53–56. (d) Iradier, F.; Arrayas, R. G.; Carretero, J. C. Org. Lett. 2001,
3, 2957–2960. (e) Krafft, M. E.; Kyne, G. M.; Hirosawa, C.; Schmidt, P.;
Abboud, K. A.; L’Helias, M. Tetrahedron 2006, 62, 11782–11792.
(6) (a) Morikawa, T.; Washio, Y.; Harada, S.; Hanai, R.; Kayashita, T.;
Nemoto, H.; Shiro, M.; Taguchi, T. J. Chem. Soc., Perkin Trans. 1 1995,
271–281. (b) Charlton, M. A.; Green, J. R. Can. J. Chem. 1997, 75, 965–
974. (c) Ogura, K.; Kayano, A.; Akazome, M. Bull. Chem. Soc. Jpn. 1997,
70, 3091–3101.
10.1021/ol8020513 CCC: $40.75
Published on Web 09/24/2008
2008 American Chemical Society

Table 1. Reaction Results from Scheme 1
compd
A
B
(A, B)
R
EWG
(yield, %)
(yield, %)
ee (%)
5, 14
Bn (1a)
SO2t-butyl (4a)
SO2Ph (4b)
COOEt (4c)
SO2t-butyl (4a)
SO2Ph (4b)
84
79
77
86
85
50
82
75
85
70
90
73
91
86
67
63
69
N/A
99a
95b
96a
95b
97a
95a
96a
99a
N/A
6, 15
Bn (1a)
7, 16
Bn (1a)
8, 17
n-butyl (1b)
n-butyl (1b)
n-butyl (1b)
t-butyl (1c)
t-butyl (1c)
t-butyl (1c)
9, 18
10, 19
11, 20
12, 21
13. 22
COOEt (4c)
SO2t-butyl (4a)
SO2Ph (4b)
COOEt (4c)
a ee values determined using chiral HPLC. b ee values determined through 1H NMR analysis of crude reaction mixture of γ-hydroxy alcohols with
(S)-Mosher acid chloride.
Recent reports on the organocatalytic, asymmetric R-se-
lenenylation of aldehydes in high yields (>85%) and high
Scheme 1
.
Synthesis of γ-Hydroxy-R,ꢀ-unsaturated Sulfones
and Esters from R-Selenyl Aldehydes11
enantiomeric excess (>95%)8 gave us an entry point to
control absolute stereochemistry in our γ-hydroxy-R,ꢀ-
unsaturated systems. Such R-selenylated aldehydes could
easily undergo an aldol-type reaction with an electron-
withdrawing group (EWG)-stabilized carbanion to give a
diastereomeric pair of γ-selenyl-ꢀ-hydroxy sulfones or esters.
Oxidation of the selenide and treatment with mild base could
give a ꢀ,γ-epoxide which, upon further treatment with base
could rearrange into the desired enantiomerically enriched
γ-hydroxy-R,ꢀ-unsaturated ester or sulfone with the overall
inversion of stereochemistry (Scheme 1, Table 1).
In order to examine the scope of this reaction, we chose three
aldehydes (3-phenylpropanal, hexanal, and 3,3-dimethylbutanal)
and three EWG-stabilized methyl groups (tert-butyl methyl
sulfone, phenyl methyl sulfone, and ethyl acetate). Using the
methodology of Tiecco and Marini8b to make R-selenyl
aldehydes 3a-c, we were able to react the crude R-selenyl
aldehyde9 with lithiated EWG-stabilized methyl groups 4a-c
to give diastereomeric compounds 5-13 (Scheme 1, A) in
55-86% yields. γ-Selenyl-ꢀ-hydroxy sulfones and esters 5-13
underwent oxidation and spontaneous cyclization with m-CPBA
and K2CO3 to give the transient ꢀ,γ-epoxide which immediately
rearranged in situ to yield exclusively the γ-hydroxy-(E)-R,ꢀ-
unsaturated sulfone or ester 14-22 (Scheme 1, B) in 63-90%
yields and excellent ee’s (g95%). The (E)-geometry of the new
carbon-carbon double bond in products 14-22 was confirmed
by H NMR spectoscopy (JR,ꢀ ) 14-16 Hz). R-Selenyl
1
aldehyde 3c derived from 3,3-dimethylbutanal underwent reac-
tion sequence A (Scheme 1) in high yield with all three EWG-
stabilized carbanions (4a-c), but γ-selenyl-ꢀ-hydroxy ester 13
derived from reaction with ethyl aceate (4c) decomposed under
the reaction conditions used in reaction sequence B (Scheme
1). Also, substituted EWG-stabilized methyl groups such as
propionates were explored, but no substantial selectivity in E/Z
double bond formation was seen.
Our success using R-selenenylated aldehydes led us to
investigate other leaving groups alpha to the aldehyde and
whether a one-pot 3-step procedure might be possible
(Scheme 2). Given the precedent for the enantioselective
organocatalytic R-chlorination of aldehydes10 we decided to
explore the feasibility of such a system in the reaction
(7) (a) Ogura, K.; Shibuya, N.; Iida, H. Tetrahedron Lett. 1981, 22,
1519–1522. (b) Pyne, S. G.; Spellmeyer, D. C.; Chen, S.; Fuchs, P. L. J. Am.
Chem. Soc. 1982, 104, 5728–5740. (c) Fuchs, P. L.; Hutchinson, D. K.
J. Am. Chem. Soc. 1985, 107, 6137–6138. (d) Ryu, I.; Kusumoto, N.; Ogawa,
A.; Kambe, N.; Sonoda, N. Organometallics 1989, 8, 2279–2281. (e)
Dominguez, E.; Carretero, J. C. Tetrahedron 1990, 46, 7197–7206. (f)
Burgess, K.; Cassidy, J.; Henderson, I. J. Org. Chem. 1991, 56, 2050–
2058. (g) Trost, B. M.; Grese, T. A. J. Org. Chem. 1991, 56, 3189–3192.
(h) Wnuk, S. F.; Dalley, N. K.; Robins, M. Can. J. Chem. 1991, 69, 2104–
2111. (i) Barton, D. L.; Gero, S. D.; Quiclet-Sire, B.; Samadi, M.
Tetrahedron: Asymmetry 1994, 5, 2123–2126. (j) Zoller, T.; Uguen, D. Eur.
J. Org. Chem. 1999, 154, 5–1550. (k) de la Rosa, V. G.; Ordonez, M.;
Llera, J. M. Tetrahedron: Asymmetry 2000, 2000, 2991–3001. (l) Marcus,
J.; Van Meurs, P. J.; Van den Nieuwendijk, M. C. H.; Porchet, M.; Brussee,
J.; Van der Gen, A. Tetrahedron 2000, 56, 2491–2495. (m) Pedersen, T. M.;
Hansen, E. L.; Kane, J.; Rein, T.; Helquist, P.; Nourby, P. O.; Tanner, D.
J. Am. Chem. Soc. 2001, 123, 9738–9742. (n) Rodriguez, S.; Vidal, A.;
Monroig, J. J.; Gonzalez, F. V. Tetrahedron Lett. 2004, 45, 5359–5361.
(8) (a) Sunden, H.; Rios, R.; Cordova, A. Tetrahedron Lett. 2007, 48,
7865–7869. (b) Tiecco, M.; Carlone, A.; Sternativo, S.; Marini, F.; Bartoli,
G.; Melchiorre, P. Angew. Chem., Int. Ed. 2007, 46, 6882–6885.
(10) (a) Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C J. Am. Chem.
Soc. 2004, 126. (b) Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.;
Jorgensen, K. A. J. Am. Chem. Soc. 2004, 126, 4790–4791.
(9) Column chromatography of the R-selenyl aldehydes, even using
Florisil, led to erosion of enantiomeric purity.
4686
Org. Lett., Vol. 10, No. 20, 2008

Scheme 2. Plan for One-Pot Procedure
Figure 1
γ-hydroxy carbon atom).
. Crystal structure of 15 (confirms R configuration at the
sequence. Individually, each step in the reaction sequence
with an R-chloro aldehyde appeared to work, but a one-pot
procedure could not be achieved successfully. Ultimately,
this strategy was not pursued due to the instability and
volatility of the R-chlorinated aldehydes and the superior
results with the R-selenyl systems.
Scheme 3
. Synthesis of (+)-R-Conhydrine (24) Using Key
Intermediate γ-Hydroxy Ether-R,ꢀ-Unsaturated Ester 235a
Confirmation of absolute stereochemistry was first achieved
by reducing R-selenyl aldehydes 3a-c with NaBH4 and
comparing optical rotations with published values.8b An
X-ray crystal structure was also obtained for γ-hydroxy-R,ꢀ-
unsaturated sulfone 15, which confirms the R configuration
of the γ-hydroxy carbon (Figure 1).
Further proving the value of this synthetic method, scale
up of the procedure to 1 g was readily accomplished with
no erosion of ee (97%) and in 59% overall yield for
γ-hydroxy-R,ꢀ-unsaturated sulfone 14.11
Scheme 4. Formal Synthesis of (+)-R-Conhydrine (24)
γ-Hydroxy ether-R,ꢀ-unsaturated ester 23 (Scheme 3) is
a key intermediate in a recent synthesis of the biologically
active alkaloid (+)-R-conhydrine (24).5a Intermediate 23 was
prepared in six steps and 32% overall yield from (S)-
glycidol.5a Using the methodology described here, we have
prepared intermediate ester 23 in only four steps and in 47%
overall yield and 97% ee (Scheme 4).
(11) Procedure for the Synthesis of 14. A solution of 3-phenylpropanal,
1a (90%, 1.2 mL, 9.4 mmol), and catalyst 2 (0.7 g, 1.2 mmol) in toluene (20
mL) was stirred at rt under Ar for 30 min. The reaction mixture was cooled to
-20 °C, and N-(phenylseleno)phthalimide (3.4 g, 11.2 mmol) was added. After
the mixture was stirred for 2 h, the contents of the flask were filtered and rinsed
with hexanes, the solvent evaporated (avoid heat!), and the crude mixture (3a)
dried under vacuum for 1 h to get rid of all toluene. To an ice-cooled solution
of methyl tert-butyl sulfone, 4a (4.0 g, 29.4 mmol), in anhydrous THF (30
mL) under Ar was added n-BuLi (1.5 M in hexanes, 18.8 mL, 28.1 mmol)
dropwise and the mixture stirred for 30 min. The reaction mixture was cooled
to -78 °C, and a solution of crude 3a (9.4 mmol) in 10 mL THF was added
via cannula. After being stirred at -78 °C for 1 h, the mixture was quenched
by addition to water (50 mL) and extracted with Et2O (3 × 30 mL). The
organics were combined, rinsed with brine (30 mL), dried over MgSO4, filtered,
concentrated, and chromatographed (25% EtOAc in hexanes) to give 5 (3.4 g,
84% yield), which was used directly in the next step. To a solution of 5 (2.5
g, 5.9 mmol) in MeOH (20 mL) was added K2CO3 (3.2 g, 23.5 mmol), and
the reaction mixture was stirred for 20 min. The mixture was cooled to 0 °C,
and m-CPBA (77%, 2.6 g, 11.8 mmol) was added. The solution was allowed
to warm slowly to rt and stirred for a total of 1.5 h. The reaction mixture was
then added to a saturated solution of NaHCO3 (25 mL) and extracted with
CH2Cl2 (3 × 30 mL). The organics were combined, dried over MgSO4, filtered,
concentrated, and chromatographed (30% EtOAc in hexanes) to give 14 (1.1
In summary, we report an efficient and generalized
procedure for the synthesis of γ-hydroxy-R,ꢀ-unsaturated
sulfones and esters of high enantiomeric purity that is easily
scaled to amounts >1 g. This three-step process works on a
variety of substrates with high overall yields (∼50%) and
excellent control of absolute stereochemistry (ee values
g95%). We have shown the application of this methodology
to a formal synthesis of the natural product (+)-R-conhy-
drine. Undoubtedly, this methodology could be expanded to
the preparation of other γ-hydroxy-R,ꢀ-unsaturated com-
pounds with other EWGs, such as nitro or cyano.
Acknowledgment. We thank the NIH (CA 93547) for
financial support and the ACS (predoctoral fellowship to
K.S.P.).
g, 70% yield) as a white solid: [R]24D -1.9 (c 1.35, CHCl3); IR (neat, cm-1
)
Supporting Information Available: Experimental pro-
cedures and spectra of γ-hydroxy-R,ꢀ-unsaturated sulfones
and esters. This material is available free of charge via the
Internet at http://pubs.acs.org.
3483 (brs), 3061 (w), 2980 (w), 2929 (w), 1630 (w), 1453 (w), 1297 (m), 1272
1
(m), 1200 (w), 1108 (m), 835 (w), 702 (w); H NMR (CDCl3, 400 MHz) δ
7.27 (m, 5H), 6.95 (dd, 1H, J ) 14.8, 3.6 Hz), 6.53 (dd, 1H, J ) 14.8, 2.0
Hz), 4.65 (m, 1H), 2.99 (dd, 1H, J ) 14.0, 5.2 Hz), 2.84 (dd, 1H, J ) 13.6,
8.0 Hz), 2.09 (brs, 1H), 1.91 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 151.05,
136. 23, 129.42, 128.82, 127.14, 123.47, 71.26, 58.42, 42.85, 23.22; HRMS
calcd for C14H20O3S [MH+] 269.1211, found 269.1211; mp ) 81-83 °C.
OL8020513
Org. Lett., Vol. 10, No. 20, 2008
4687