Vinylaluminum addition to sulfinimines (N-sulfinyl imines). Asymmetric synthesis of anti-α-alkyl β-amino esters

Article abstract of DOI:10.1021/jo9001504

Addition of vinylaluminum NMO reagents to N-(p-toluenesufinyl)- and N-(2-methypropanesulfinyl)-derived sulfinimines gives N-sulfinyl aza-Morita-Baylis-Hillman products (dr ) 7:1 to 12:1) that result from addition of the reagent from the least hindered dir

Full text of DOI:10.1021/jo9001504

Vinylaluminum Addition to Sulfinimines (N-Sulfinyl Imines).
Asymmetric Synthesis of anti-r-Alkyl ꢀ-Amino Esters
Franklin A. Davis,* Hui Qiu, Minsoo Song, and Narendra V. Gaddiraju
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122
fdaVis@temple.edu
ReceiVed January 23, 2009
Addition of vinylaluminum NMO reagents to N-(p-toluenesufinyl)- and N-(2-methypropanesulfinyl)-
derived sulfinimines gives N-sulfinyl aza-Morita-Baylis-Hillman products (dr ) 7:1 to 12:1) that result
from addition of the reagent from the least hindered direction. Hydrogenation of the aza-MBH adducts
with a Rh(I) catalyst affords anti-R-substituted N-sulfinyl-ꢀ-amino esters in good yield and high dr (10:1
to 21:1).
Introduction
The development of new and improved methodologies for
the asymmetric synthesis of ꢀ-amino acids continues to be an
important objective because of their valuable biological proper-
ties and their utility as chiral building blocks and as precursors
of ꢀ-lactams.1,2 Substitution of ꢀ-amino acids for R-amino acids
results in ꢀ-peptides with novel activity and increased enzyme
stability.3 For these reasons, many methods have been devised
for the synthesis of ꢀ-amino acids,1,2 including the diastereo-
selective addition of enolates to enantiopure sulfinimines (N-
sulfinyl imines).4 However, only a few methods have been
reported for the enantioselective synthesis of acyclic R-substi-
tuted ꢀ-amino acids.1,5
FIGURE 1. Retrosynthetic approach to R-substituted N-sulfinyl ꢀ-ami-
no esters.
As part of a program aimed at the asymmetric synthesis of
N-sulfinyl R-substituted ꢀ-amino esters and ketones, we have
been exploring the addition of prochiral Weinreb amide enolates
to sulfinimines.5a Another way to access these compounds is
the stereoselective reduction of sulfinimine-derived R-(ami-
noalkyl)acrylates (aza-Morita-Baylis-Hillman) adducts (Figure
1).6 However, sulfinimines have rarely been employed in the
aza-Morita-Baylis-Hillman (aza-MBH) reaction.7 Aggarwal
et al. reported the 7 day reaction of methyl acrylate with
sulfinimines to give aza-MBH adducts with modest diastereo-
selectivity and yield.8 In the presence of PhPMe2, cyclopent-
2-eneone reacts with aromatic aldehyde-derived sulfinimines to
give aza-MBH adducts with poor to good diastereoselectivity.9
(1) For a review, see: (a) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991.
(2) Juaristi, E.; Lopez-Ruiz, H. Curr. Med. Chem. 1999, 3, 2037.
(3) (a) For recent reviews on ꢀ-peptides, see: Seebach, D; Gardiner, J. Acc.
Chem. Res. 2008, 41, 1366. (b) Aguilar, M-I.; Purcell, A. W.; Devi, R.; Lew,
R.; Rossjohn, J.; Smith, A. I.; Perlmutter, P. Org. Biomol. Chem. 2007, 5, 2884.
(c) Fulop, F.; Martinek, T. A.; Toth, G. K. Chem. Soc. ReV. 2006, 35, 323.
(4) For reviews of sulfinimine chemistry which also include discussions of
ꢀ-amino acid syntheses, see: (a) Morton, D.; Stockman, R. A. Tetrahedron 2006,
62, 8869. (b) Davis, F. A. J. Org. Chem. 2006, 71, 8993. (c) Senanayake, C. H.;
Krishnamurthy, D.; Lu, Z.-H.; Han, Z.; Gallou, I. Aldrichimica Acta 2005, 38,
93. (d) Zhou, P.; Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003. (e)
Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984.
(5) For the application of sulfinimines in the asymmetric synthesis of R-alkyl-
ꢀ-amino acids, see: (a) Davis, F. A.; Song, M. Org. Lett. 2007, 9, 2413. (b)
Tang, T. P.; Ellman, J. A. J. Org. Chem. 2002, 67, 7819. (c) Garcia Ruano,
J. L.; Fernandez, I.; del Prado Catalina, M.; Hermoso, J. A.; Sanz-Aparicio, J.;
Martinez-Ripoll, M. J. Org. Chem. 1998, 63, 7157.
(7) Thermal elimination of benzenesulfenic acid from R-phenylsulfinylmethyl-
ꢀ-(N-sulfinylamino) esters is reported to give R-methylene-ꢀ-(N-sulfinyamino)
esters. See: Kamimura, A.; Okawa, H.; Morisaki, Y.; Ishikawa, S.; Undo, H. J.
Org. Chem. 2007, 72, 3569.
(8) Aggarwal, V. K.; Castro, A. M. M.; Mereu, A; Adams, H. Tetrahedron
Lett. 2002, 43, 1577.
(9) Shi, M.; Xu, Y.-M. Tetrahedron: Asymmetry 2002, 13, 1195.
(6) For a review on the Morita-Baylis-Hillman reaction, see: Basavaiah,
D.; Rao, A. J.; Satyanarayana, T. Chem. ReV. 2003, 103, 811.
2798 J. Org. Chem. 2009, 74, 2798–2803
10.1021/jo9001504 CCC: $40.75 2009 American Chemical Society
Published on Web 03/09/2009

Vinylaluminum Addition to Sulfinimines
SCHEME 1
In the sulfinimine-mediated aza-MBH reaction,8,9 Re face
addition of the vinyl anion species to (S)-(+)-3 gave the aza-
MBH product having the S-configuration at the new C-N
stereogenic center.8,9,11 However, the 1H NMR of these products
and (+)-4 were significantly different, suggesting that they were
different compounds. For example, the vinyl protons in (+)-4
appear at δ 6.02 and 6.48 ppm, whereas in the (SS,S) aza-MBH
adduct reported by Aggrawal, these protons appear at δ 5.8 and
6.4 ppm, respectively.8
TABLE 1. Reaction of (S)-(+)-3 with [r-(Ethoxycarbonyl)vinyl]-
diisobutylaluminum (2) at 0 °C in THF for 6 h
conditions (equiv)a1/
DIBAL-H/NMO
(+)-4 %
entry
drb
isolated yieldc
1
2
3
1:1.5:2.0
3.0:4.5:6.0
3.0:4.5:6.0 [3 Zn(OTf)2]
9:1
7:1
8:1
17
65
63
a Equivalents based on sulfinamide (+)-3. b Determined by 1H NMR
on the crude reaction mixture. c Isolated yield of major diastereoisomer.
Because (+)-4 is an oil, it was not possible to determine its
absolute configuration by X-ray analysis, and therefore, it was
necessary to convert it into products of known absolute
stereochemistry. This requires the stereoselective reduction of
the R-methylene group in (+)-4 to a methyl group. The
homogeneous hydrogenation of Baylis-Hillman adducts has
been reported and generally gives anti products.6,13 Hydrogena-
tion of N-acyl ꢀ-amino-R-methylene esters using Rh(II) and
Rh(I) catalysts at high pressure (30 atm) gives the corresponding
anti-R-substituted ꢀ-amino esters.14 However, there are no
reports of the reduction of N-sulfinyl ꢀ-amino-R-methylene
esters.
Hydrogenation of (+)-4 at rt using 7.5 mol % of cationic
rhodium complex A for 48 h gave a 22:1 mixture of diastere-
oisomers with isolation of the major diastereoisomer (SS,2R,3S)-
(+)-5 in 88% yield (Scheme 2). Oxidation with m-CPBA gave
(2R,3S)-(-)-7, and hydrolysis afforded the known acid (2R,3S)-
(-)-8 in 87% yield.15 To further confirm the trans stereochem-
istry, the acid was treated with DCC/4-pyrrolidinopyridine to
give ꢀ-lactam (3R,4S)-(-)-9, also a known compound (Scheme
2).15a In (-)-9, the J3,4 coupling constant was 3.2 Hz and similar
to the reported value of 3.0 Hz (cis ) J3,4 ) 6 Hz).15a These
results indicate that the vinylaluminum reagent adds to the Si
face in sulfinimine (S)-(+)-3. Formation of the anti product
(+)-5 is consistent with coordination of the Rh catalyst A with
the sulfinyl nitrogen atom and addition of hydrogen from the
more hindered face of the C-C double bond.1314
More recently, Scheidt and co-workers described the addition
of lithium allenolates, in the presence of HMPA, to sulfinimines
affording ꢀ-substituted aza-MBH products in good yield and
high selectivity.10
In a series of papers, Li and co-workers explored the addition
of vinylcuprates, prepared by Michael addition of R2CuLi to
R-acetylenic esters, to sulfinimines at -23 °C to give novel
branched aza-MBH adducts.11 For the addition to occur,
stoichiometric amounts of Et2AlCl or 40 mol % of Yb(OTf)3
were required. Careful control of the reaction conditions was
also necessary for good yields.11 These workers also reported
that vinylaluminum reagents were unreactive.11c Ramachandran
and co-workers described a new procedure for the synthesis of
vinylaluminum reagents from DIBAL-H, R-acetylenic esters,
and 4-methylmorpholine N-oxide (NMO).12 These workers
demonstrated that their vinylaluminum reagents gave good
yields of MBH adducts on reaction with aldehydes and ketones.
Inspired by these studies, we describe the application of this
protocol to the asymmetric syntheses of N-sulfinyl R-(ami-
noalkyl)acrylates (aza-Morita-Baylis-Hillman products) and
their stereoselective reduction to N-sulfinyl-R-substituted ꢀ-ami-
no esters.
Results and Discussion
Following the Ramachandran procedure, an NMO (2.0 equiv)
THF solution was added to a THF solution of DIBAL-H (1.5
equiv) at 0 °C to give a clear solution. After 1 h, to this solution
were added 1.0 equiv of ethyl propiolate (1) and l.0 equiv of
(S)-(+)-N-(benzylidene)-p-toluenesufinamide (3) (Scheme 1).
(SS,R)-(-)-Ethyl-2-[phenyl-(p-toluenesulfinylamino)methyl]acr-
ylate (4) was formed as a 9:1 mixture of diastereoisomers, but
the isolated yield of the major diastereoisomer was low (Table
1, entry 1). When the amount of the vinylaluminum reagent 2
was increased 3-fold the yield of (+)-4 improved to 65%. Use
of Zn(OTf)2 in these reactions had little or no effect on the yield
or diastereoselectivity. These results are summarized in Table
1.
Structures resulting from the addition of organometallic
reagents to the C-N double bond of sulfinimines can generally
be predicted by assuming chelated, chairlike transition states
resulting from coordination of the metal ion with the sulfinyl
oxygen. The sulfinimine-mediated aza-MBH reaction9 and the
addition of vinylcuprates11 to sulfinimines are in agreement with
this transition state hypothesis. However, there are exceptions
where the organometallic reagent adds to the C-N double bond
from the least hindered direction, away from the bulky sulfinyl
(13) Brown, J. M. Angew. Chem., Int. Ed. Engl. 1987, 26, 190.
(14) Yamamoto, K.; Takagi, M.; Tsuji, J. Bull. Chem. Soc. Jpn. 1988, 61,
319.
(15) (a) Abrahams, I.; Motevalli, M.; Robinson, A. J.; Wyatt, P. B.
Tetrahedron 1994, 50, 12755. (b) Roos, G. H. P.; Balasubramaniam, S. Synth.
Commun. 1999, 29, 755.
(16) (a) Mikolajczyk, M.; Lyzwa, P.; Drabowicz, J.; Wieczorek, M. W.;
Blaszcsyk, J. Chem. Commun. 1996, 1503. (b) Davis, F. A.; McCoull, W. J.
Org. Chem. 1999, 64, 3396. (c) Davis, F. A.; Wu, Y.; Yan, H.; McCoull, W.;
Prasad, K. R. J. Org. Chem. 2003, 68, 2410.
(10) Reynolds, T. E.; Binkley, M. S.; Scheidt, K. A. Org. Lett. 2008, 10,
5227.
(11) (a) Wei, H.-X.; Hook, J. D.; Fitzgerald, K. A.; Li, G. Tetrahedron:
Asymmetry 1999, 10, 661. (b) Li, G.; Wei, H.-X.; Hook, J. D. Tetrahedron Lett.
1999, 40, 4611. (c) Li, G.; Wei, H.-X.; Whittlesey, B. R.; Batrice, N. N. J. Org.
Chem. 1999, 64, 1061.
(12) Ramachandran, P. V.; Rudd, M. T.; Burghardt, T. E.; Reddy, M. V. R.
J. Org. Chem. 2003, 68, 9310.
J. Org. Chem. Vol. 74, No. 7, 2009 2799

Davis et al.
SCHEME 2
TABLE 2. Reaction of Propargylic Esters 1, 10, and 11 with Sulfinimines (+)-(S)-3 and (-)-(R)-12
entry
sulfinamide
1, 10, or 11/DIBAL-H/NMO (equiv)
temp, °C (h)
products, % yielda (dr)b
1
2
3
4
5
6
7
8
9
10
(+)-3
(10: R ) Me) 3.0:4.5:6.0
(1: R ) H) 3.0:4.5:6.0
(1: R ) H) 3.0:4.5:6.0
(1: R ) H) 3.0:4.5:6.0
(1: R ) H) 3.0:4.5:6.0
(10: R ) Me) 3.0:4.5:6.0
(11: R ) Ph) 3.0:4.5:6.0
(1: R ) H) 3.0:4.5:6.0
(10: R ) Me) 3.0:4.5:6.0
(11: R ) Ph) 3.0:4.5:6.0
25 (16)
25 (6)
13, 61 (5:1)c
no reaction
(-)-12a (R′ ) Ph)
(-)-12b (R′ ) Et)
25 (23)
45 (15)
70 (15)
70 (15)
70 (15)
70 (15)
70 (15)
70 (15)
14a, 41 (3:1)
14a, 38 (12:1)
14a, 65 (12:1)
14b, 71 (7:1)
14c, 73 (7:1)
14d, 58 (13:1)c d
,
14e, 50 (11:1)c d
,
14f, 35 (6.2:1)
a Isolated yield of major diastereoisomer. b Determined by 1H NMR on the crude reaction mixture. c Inseparable isomers. d Determined by 1H NMR
on the mixture after purification.
group.16 As previously suggested by us, a Yamamoto-type
model TS-A (Figure 2), where the vinylaluminum reagent adds
to the Si face of the C-N double bond, explains our results.16b
We suggest that the added NMO, which acts as a ligand to
aluminum to suppress the tendency of DIBAL-H to reduce CdO
and CdN groups,17 also prevents complexation of aluminum
with the sulfinyl group. In the presence of HMPA, lithium
allenolates also add to the Si face of sulfinimines.10
The addition of ꢀ-substituted vinylaluminum reagents to
sulfinimines was next examined. Addition of [R-(ethoxycarbo-
nyl)-ꢀ-methylvinyl]diisobutylaluminum, prepared from prop-
argylic ester 10, afforded 13 as a 5:1 mixture of inseparable
diastereoisomers (Table 2, entry 1). In the past, we have solved
this separation problem by changing the N-sulfinyl auxiliary.18
However, reaction of 2 with (RS)-(-)-N-(benzylidene)-2-me-
thylpropanesulfinamide (12a) at rt resulted in no reaction (Table
2, entry 2). When the temperature was increased to 70 °C for
15 h, compound (RS,S)-(-)-14a was obtained as a 12:1 mixture
of diastereoisomers with isolation of the major diastereoisomer
in 65% yield (Table 2, entry 5).19 Under these conditions,
addition of [R-(ethoxycarbonyl)-ꢀ-methylvinyl]diisobutylalu-
minum and [R-(ethoxycarbonyl)-ꢀ-phenylvinyl]diisobutylalu-
minum to (-)-12a gave (RS,S)-(-)-14b and (RS,S)-(-)-14c,
respectively, as 7:1 mixtures of diastereoisomers. The major
diastereoisomers were isolated in 71 and 73% yields (Table 2,
entries 6 and 7). Similar results were observed for addition of
the ꢀ-substituted vinylaluminum reagents to (RS)-(-)-N-(eth-
ylidene)-2-methylpropanesulfinamide (12b) to give 14d (R )
H), 14e (R ) Me), and 14f (R ) Ph). However, the diastere-
oisomers of 14d (13:1) and 14e (11:1) could not be separated
(17) Tsuda, T.; Yoshida, T.; Kawamoto, T.; Saegusa, T. J. Org. Chem. 1987,
52, 1624.
(18) Davis, F. A.; Song, M. Org. Lett. 2007, 9, 2413.
(19) The absolute stereochemistry of (RS,S)-14a was established by trans-
forming it into the enantiomer of (2R,3S)-(-)-7 isomer (2S,3R)-(+)-7 by
hydrogenation with catalyst A (90%), removal of the sulfinyl group with HCl-
H2O, and conversion into the Ts sulfonamide with Ts-Cl, Et3N, and DMAP
(79%). See Experimental Section.
(20) Ramachandran, P. V.; Reddy, M. V. R.; Rudd, M. T.; de Alaniz, J. R.
Tetrahedron Lett. 1998, 39, 8791.
(21) For leading references to the asymmetric synthesis of anti-R-substituted
ꢀ-amino esters via the R-alkylation of ꢀ-amino esters dianions, see: (a) Wang,
J.; Hou, Y.; Wu, P.; Qu, Z.; Chan, A. S. C. Tetrahedron: Asymmetry 1999, 10,
4553. See also: (b) McNeil, A. J.; Toombes, G. E. S.; Gruner, S. M.; Lobkovsky,
E.; Collum, D. B.; Chandramouli, S. V.; Vanasse, B. J.; Ayers, T. A. J. Am.
Chem. Soc. 2004, 126, 16559.
2800 J. Org. Chem. Vol. 74, No. 7, 2009

Vinylaluminum Addition to Sulfinimines
SCHEME 3
TABLE 3. Hydrogenation of aza-Morita-Baylis-Hillman
Adducts with Catalysts A
SCHEME 4
time (h),
atm of H2
entry
>14 (R′, R)
>solvent
CH2Cl2
>15 dr (% yield)a
15a, 21:1 (83)
1
2
3
4
5
6
14a (Ph, H)
14b (Ph, Me)
14c (Ph, Ph)
14d (Et, H)
14e (Et, Me)
14f (Et, Ph)
48, 1
72, 25
72, 25
48, 1
72, 25
72, 25
ClCH2CH2Cl 15b, 20:1 (81)
ClCH2CH2Cl 15c, 20:1 (79)
CH2Cl2
15d, 10:1 (55)
ClCH2CH2Cl 15e, decomposition
ClCH2CH2Cl 15d, 17:1 (79)
a Isolated yield of major diastereoisomer.
substituted N-sulfinyl-ꢀ-amino esters and is a useful new method
for their preparation.21,22
Experimental Section
Sulfinimines (S)-(+)-N-(benzylidene)-p-toluenesulfinamide (3),23
(R)-(-)-N-(benzylidene)-2-methylpropanesulfinamide (12a),24 and
(R)-(-)-N-(propylidene)-2-methylpropanesulfinamide (12b)24 were
prepared as previously described. Catalyst (bicyclo[2.2.1]hepta-2,5-
diene)[1,4-bisdiphenylphosphino)butanerhodium(I) tetrafluoroborate
A was purchased from Aldrich.
FIGURE 2. Model for the addition of vinylaluminum to the Si face of
(S)-(+)-3.
(Scheme 3 and Table 2, entries 8-10). On the basis of earlier
studies, the stereochemistry 14 is expected to be Z.12,20 Upon
irradiation of the C-3 vinyl proton at δ 6.28 ppm in (-)-14b, a
positive NOE was observed on the C-2 amine proton at δ 5.28
(8.3%), consistent with Z olefin geometry.
Hydrogenation of 14 as before gave 15 in good yield (Table
3). When R was hydrogen, reduction was complete within 48 h
at rt and 1 atm of H2 (Table 3, entries 1 and 4). When R in 14
was Me or Ph, longer times (72 h) and higher pressures of H2
(25 atm) were necessary. ꢀ-Amino ester 15e was formed as a
mixture of inseparable diastereoisomers contaminated with
starting material (Scheme 4). Prolonged hydrogenation (>90 h)
resulted in decomposition.
(SS,2R)-(+)-Ethyl 2-[phenyl(p-toluenesulfinylamino)methyl]acr-
ylate (4). In a 50 mL, dry, single-necked round-bottom flask
equipped with a magnetic stirring bar, rubber septum, and argon
balloon was placed NMO (0.696 g, 5.92 mmol) in THF (8 mL),
and the solution was cooled to 0 °C. To the solution was added
DIBAL-H (4.48 mL, 1.0 M in THF) at 0 °C, and the mixture was
stirred at this temperature for 0.5 h before ethyl propiolate (1) (0.304
mL, 2.96 mmol) was added. The mixture was stirred for 1 h at 0
°C, and a solution of (S)-(+)-3 (0.240 g, 0.984 mmol) in THF (8
mL) was added. The mixture was warmed to rt, stirred for 4 h,
quenched with Rochelle salt (NaKC4H4O6 ·H2O) (10 mL), diluted
with EtOAc (15 mL), and vigorously stirred for 30 min. At this
time, the solution was extracted with EtOAc (3 × 15 mL), and the
combined organic phases were washed with brine (5 mL), dried
(MgSO4), and concentrated. Flash chromatography (50% EtOAc/
In summary, reaction of vinylaluminum NMO reagents with
sulfinimines gives N-sulfinyl aza-Morita-Baylis-Hillman prod-
ucts that result from addition of the reagent from the least
hindered direction via a nonchelation control mechanism.
Hydrogenation of the aza-MBH adducts affords anti-R-
hexanes) provided 0.220 g (65%) of a colorless oil: [R]20 +30.0
D
(23) (a) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G. V.;
Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou, P.; Carroll, P. J.
Org. Chem. 1997, 62, 2555. (b) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang,
T.; Fanelli, D.; Zhang, H. J. Org. Chem. 1999, 64, 1403. (c) Finelli, D. L.;
Szewczyk, J. M.; Zhang, Y.; Reddy, G. V.; Burns, D. M.; Davis, F. A. Org.
Synth. 2004, 10, 47.
(22) For other methods for the asymmetric synthesis of anti-R-substituted
ꢀ-amino esters, see: (a) Davies, S. G.; Walters, I. A. S. J. Chem. Soc., Perkin
Trans. 1 1994, 1129. (b) Sibi, M. P.; Prabagaran, N.; Ghorpade, S. G.; Jasperse,
C. P. J. Am. Chem. Soc. 2003, 125, 11796. (c) Ainara, I.; Vicario, J. L.; Carrillo,
L.; Badia, D. Synthesis 2006, 4065. (d) Ref 5c.
(24) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119,
9913.
J. Org. Chem. Vol. 74, No. 7, 2009 2801

Davis et al.
(c 0.28, CHCl3); IR (neat) 3204, 1711, 1053 cm-1
;
1H NMR
60.1, 56.1, 29.1, 22.9, 14.5, 11.3; HRMS calcd for C12H24NO3S
(M + H) 262.1477, found 262.1455.
(CDCl3) δ 7.61 (d, J ) 6.4 Hz, 2H), 7.24 (m, 7H), 6.47 (s, 1H),
6.03 (d, J ) 0.8 Hz, 1H), 5.35 (d, J ) 7.2 Hz, 2H), 4.93 (d, J )
7.2 Hz, 1H), 4.13 (q, J ) 7.2 Hz, 2H), 2.39 (s, 3H), 1.20 (t, J )
6.8 Hz, 3H); 13C NMR δ 166.0, 141.8, 141.6, 140.5, 129.9, 128.9,
128.0, 127.4, 127.2, 126.0, 61.3, 58.4, 21.7, 14.5 (one carbon could
not be identified due to overlap); HRMS calcd for C19H22NO3S (M
+ H) 344.1320, found 344.1327.
(Z)-(RS,3S)-(-)-Ethyl 3-(1,1-Dimethylethylsulfinamido)-2-eth-
ylidenepentanoate (14e). Flash chromatography (40% EtOAc/
hexanes) provided 50% of a colorless oil: [R]20 -51.5 (c 1.20,
D
1
CHCl3); IR (neat) 3224, 1714, 1454, cm-1; H NMR (CDCl3) δ
6.11 (m, 1H), 4.21 (m, 2H), 3.87 (q, J ) 6.8 Hz, 1H), 3.58 (d, J )
6.0 Hz, 1H), 1.97 (d, J ) 6.8 Hz, 3H), 1.79 (m, 2H), 1.31 (t, J )
7.2 Hz, 3H), 1.17 (s, 9H), 0.90 (t, J ) 7.2 Hz, 3H); 13C NMR
(CDCl3) δ 167.5, 137.7, 133.8, 62.6, 60.7, 55.9, 29.4, 22.9, 15.8,
14.6, 11.3; HRMS calcd for C13H26NO3S (M + H) 276.1633, found
276.1635.
Ethyl (Rs,2S)-(-)-2-[Phenyl-(2-methylpropanesulfinylamino)-
methyl]acrylate (14a). In a 50 mL, flame-dried, single-necked
round-bottomed flask equipped with a magnetic stirring bar, rubber
septum, a reflux condenser, and argon balloon was placed NMO
(0.606 g, 5.16 mmol) in THF (6 mL). To the solution was added
DIBAL-H (3.9 mL, 1.0 M solution in THF) at 0 °C, and the mixture
was stirred for 30 min. Ethyl propiolate (1) (0.264 mL, 2.59 mmol)
was added via syringe, and the mixture was stirred for 1 h at 0 °C,
and (R)-(-)-12a (0.180 g, 0.864 mmol) in anhydrous THF (6 mL)
was added. The mixture was heated to 70 °C and stirred for 15 h,
cooled to rt, quenched by addition of saturated aqueous Rochelle
salt (10 mL), diluted with EtOAc (15 mL), and stirred vigorously
for 0.5 h. The organic phase was washed with brine (5 mL), dried
(MgSO4), and concentrated. Flash chromatography (25% EtOAc/
Ethyl (Z)-(RS,2S)-(-)-2-[Ethyl(2-methylpropanesulfinylami-
no)methyl]-3-phenylacrylate (14f). Flash chromatography (50%
EtOAc/hexanes) provided 35% of a colorless oil: [R]20 -36.3 (c
D
1
0.84, CHCl3); IR (KBr) 3211, 1722, 1225, 1061 cm-1; H NMR
(CDCl3) δ 7.22 (m, 5H), 6.77 (s, 1H), 4.07 (m, 3H), 3.47 (d, J )
5.2 Hz, 1H), 1.98 (m, 1H), 1.83 (m, 1H), 1.20 (s, 9H), 1.06 (t, J )
7.2 Hz, 3H), 1.02 (t, J ) 7.6 Hz, 3H); 13C NMR (CDCl3) δ 168.7,
135.7, 135.3, 134.8, 128.7, 128.6 128.5, 62.7, 61.1, 56.1, 29.3, 22.9,
14.0, 11.4; HRMS calcd for C18H28NO3S (M + H) 338.1790, found
338.1781.
hexanes) provided 0.174 g (65%) of a colorless oil: [R]20 -1.40
(SS,2R,3S)-(+)-Ethyl 2-Methyl-3-(4-methylphenylsulfinamido)-
3-phenylpropanoate (5). In an oven-dried, 25 mL one-neck round-
bottomed flask equipped with a magnetic stirring bar, rubber
septum, and a H2 balloon were placed (+)-4 (0.200 g, 0.585 mmol)
and rhodium complex A (0.031 g, 0.044 mmol) in anhydrous DCM
(5.0 mL). The solution was evacuated and filled with H2, and this
sequence was repeated five times. The reaction mixture was stirred
for 48 h at rt and concentrated. Flash chromaatography (50%
EtOAc/hexanes) afforded 0.180 g (88%) of a colorless oil: [R]20
D
(c 0.93, CHCl3); IR (KBr) 3233, 2980, 1717, 1061 cm-1; 1H NMR
(CDCl3) δ 7.26 (m, 5H), 6.45 (s, 1H), 5.99 (s, 1H), 5.49 (d, J )
4.8 Hz, 1H), 4.12 (m, 2H), 3.76 (d, J ) 4.8 Hz, 1H), 1.25 (s, 9H),
1.20 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3) δ 166.0, 141.6, 140.7,
129.1, 128.3, 127.9, 126.8, 61.3, 59.8, 56.5, 23.0, 14.4; HRMS calcd
for C16H24NO3S (M + H) 310.1477, found 310.1472.
(Z)-Ethyl (RS,2S)-(-)-2-[Phenyl-(2-methylpropanesulfinylami-
no)methyl]but-2-enoate (14b). General Procedure. In a 50 mL,
flame-dried, single-necked round-bottomed flask equipped with a
magnetic stirring bar, rubber septum, a reflux condenser, and argon
balloon was placed NMO (0.606 g, 5.16 mmol) in THF (6 mL).
The solution was cooled to 0 °C, DIBAL-H (3.9 mL, 1.0 M solution
in THF) was added, and the reaction mixture was stirred for 30
min at which time ethyl but-2-ynoate (10) (0.300 mL, 2.59 mmol)
was added via syringe. After stirring for 4 h at rt, (R)-(-)-12a (0.180
g, 0.864 mmol) in THF (6 mL) was added. The reaction mixture
was heated to 70 °C, stirred for 15 h, cooled to rt, and quenched
by addition of saturated aqueous Rochelle salt (10 mL). The solution
was diluted with EtOAc (15 mL), vigorously stirred, and the organic
phase was washed with brine (5 mL), dried (MgSO4), and
concentrated. Flash chromatography (33% EtOAc/hexanes) pro-
+33.6 (c 0.65, CHCl3); IR (neat) 3206, 1730, 1090, 1053 cm-1D
;
1H NMR (CDCl3) δ 7.43 (d, J ) 8.0 Hz, 2H), 7.21 (m, 3H), 7.11
(m, 4H), 5.06 (d, J ) 7.2 Hz, 1H), 4.50 (dd, J ) 7.2, 8.0 Hz, 1H),
4.13 (q, J ) 7.2 Hz, 2H), 2.88 (dq, J ) 6.8, 8.0 Hz, 1H), 2.32 (s,
3H), 1.21 (t, J ) 7.2 Hz, 3H), 1.46 (d, J ) 6.8 Hz, 3H); 13C NMR
δ 175.0, 142.0, 141.4, 141.1, 129.5, 129.0, 127.9, 127.3, 126.1,
61.1, 60.4, 46.9, 21.6, 15.8, 14.5; HRMS calcd for C19H23NO3SNa
(M + Na) 368.1296, found 368.1304.
(RS,2S,3R)-(-)-Ethyl 2-Methyl-3-(4-methylphenylsulfinamido)-
3-phenylpropanoate (15a). Flash chromatograpy (50% EtOAc/
hexanes) afforded 83% of a colorless oil: [R]20 -20.6 (c 0.18,
D
1
CHCl3); IR (neat) 3584, 3256, 1734 cm-1; H NMR (CDCl3) δ
7.32 (m, 5H), 4.46 (dd, J ) 8.4, 8.4 Hz, 1H), 4.12 (q, J ) 7.3 Hz,
2H), 3.96 (d, J ) 8.4 Hz, 1H), 2.92 (dq, J ) 7.2, 8.4 Hz, 1H), 1.24
(t, J ) 7.2 Hz, 3H), 1.11 (s, 9H), 0.99 (d, J ) 6.8 Hz, 3H); 13C
NMR (CDCl3) δ 174.9, 140.4, 128.9, 128.2, 127.4, 63.1, 60.8, 56.4,
46.8, 22.7, 15.2, 14.3; HRMS calcd for C16H26NO3S (M + H)
312.1633, found 312.1625.
vided 0.329 g (71%) of a colorless oil: [R]20 -24.8 (c 0.29,
D
CHCl3); IR (KBr) 3214, 3030, 2959, 2869, 1717 cm-1; H NMR
1
(CDCl3) major isomer δ 7.25 (m, 5H), 6.35 (q, J ) 7.2 Hz, 1H),
5.34 (d, J ) 6.4 Hz, 1H), 4.09 (m, 2H), 3.85 (d, J ) 6.4 Hz, 1H),
2.05 (dd, J ) 0.8, 7.2 Hz, 3H), 1.23 (s, 9H), 1.15 (t, J ) 7.0 Hz,
3H); 13C NMR (CDCl3) δ 166.7, 141.0, 138.8, 133.8, 128.7, 127.8,
127.4, 61.9, 60.5, 56.2, 22.8, 15.7, 14.2; HRMS calcd for
C17H26NO3S (M + H) 324.1633, found 324.1649.
(RS,S)-(-)-Ethyl 2-[(R)-(1,1-Dimethylethylsulfinamido)(phe-
nyl)methyl]butanoate (15b). In an oven-dried, 25 mL one-necked,
round-bottomed flask equipped with a magnetic stirring bar were
placed (-)-14b (0.0302 g, 0.093 mmol) and rhodium complex A
(0.005 g, 0.007 mmol) in 1,2-dichloroethane (4.5 mL). The solution
was placed in a high-pressure vessel (Series 4650 2.50 Inch Inside
Diameter HP/HT from Parr Instrument Company). The vessel was
tightly closed and was filled with H2 until the inner pressure reached
25 atm at which time it was evacuated and refilled with H2 to 25
atm. This sequence was repeated three times. The reaction mixture
was stirred at 25 atm of H2 for 72 h at rt, at which time the solution
was concentrated. Preparative TLC (50% EtOAc/hexanes) afforded
(Z)-Ethyl (Rs,2R)-(-)-2-[Phenyl(2-methylpropanesulfinylami-
no)methyl]-3-phenylacrylate (14c). Flash chromatography (25%
EtOAc/hexanes) provided 73% of a colorless oil: [R]20 -41.0 (c
D
1.05, CHCl3); IR (KBr) 3211, 1734, 1225 cm-1; 1H NMR (CDCl3)
δ 7.46 (m, 2H), 7.36 (m, 3H), 7.28 (m, 5H), 6.94 (s, 1H), 5.45 (d,
J ) 6.0 Hz, 1H), 4.00 (m, 2H), 3.91 (d, J ) 6.0 Hz, 1H), 1.27 (s,
9H), 0.97 (t, J ) 7.0 Hz, 3H); 13C NMR (CDCl3) δ 168.1, 139.9,
135.7, 135.4, 134.9, 128.8, 128.6, 128.5, 128.3, 128.2, 127.7, 62.7,
60.9, 56.4, 22.8 (3C), 13.7; HRMS calcd for C22H28NO3S (M +
H) 386.1790, found 386.1805.
0.0241 g (81%) of a colorless oil: [R]20 -44.4 (c 0.41, CHCl3);
D
1
(RS,3S)-(-)-Ethyl 3-(1,1-Dimethylethylsulfinamido)-2-methyl-
IR (neat) 3216, 1732, 1052 cm-1; H NMR (CDCl3) δ 7.30 (m,
enepentanoate (14d). Flash chromatography (40% EtOAc/hexanes)
5H), 4.60 (dd, J ) 7.6, 7.6 Hz, 1H), 3.95 (q, J ) 7.2 Hz, 2H), 3.66
(d, J ) 7.6 Hz, 1H), 2.80 (m, 1H), 1.63 (m, 2H), 1.20 (s, 9H), 1.04
(t, J ) 7.2 Hz, 3H), 0.92 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3)
δ 173.0, 140.6, 128.6, 128.0, 127.3, 61.7, 60.4, 56.5, 54.2, 22.7,
22.1, 14.0, 11.9; HRMS calcd for C17H28NO3S (M + H) 326.1790,
found 326.1782.
provided 55% of a colorless oil: IR (neat) 3212, 1718 cm-1; [R]20
D
1
-39.6 (c 1.26, CHCl3); H NMR (CDCl3) δ 6.26 (s, 1H), 5.27 (s,
1H), 4.22 (m, 2H), 4.04 (dt, J ) 6.8 Hz, 1H), 3.68 (d, J ) 6.8 Hz,
1H), 1.86 (m, 2H), 1.31 (t, J ) 6.8 Hz, 3H), 1.19 (s, 9H), 0.93 (t,
J ) 7.6 Hz, 3H); 13C NMR (CDCl3) δ 166.4, 141.3, 126.3, 61.2,
2802 J. Org. Chem. Vol. 74, No. 7, 2009

Vinylaluminum Addition to Sulfinimines
(RS,2S,3R)-(-)-Ethyl 2-Benzyl-3-(1,1-dimethylethylsulfinamido)-
3-phenylpropanoate (15c). Preparative TLC (50% EtOAc/hexanes)
afforded 79% of a colorless oil: [R]20D -19.5 (c 0.57, CHCl3); IR
(neat) 3221, 1730, 1052 cm-1; 1H NMR (CDCl3) δ 7.30 (m, 10H),
4.66 (dd, J ) 7.2, 7.2 Hz, 1H), 3.81 (m, 3H), 3.20 (m, 1H), 3.06
balloon in DCM (5.2 mL). TsCl (0.067 g, 0.531 mmol) was added,
the solution was cooled to 0 °C, and Et3N (0.1 mL, 0.708 mmol)
and DMAP (2.1 mg, 0.0177 mmol) were added. The reaction
mixture was warmed to rt, stirred for 12 h, and quenched with H2O
(3 mL). The solution was extracted with DCM (3 × 5 mL), and
the combined organic phases were washed with brine (5 mL), dried
(MgSO4), and concentrated. Chromatography (25% EtOAc/hexanes)
(m, 1H), 2.92 (m, 1H), 1.23 (s, 9H), 0.89 (t, J ) 7.2 Hz, 3H); 13
C
NMR (CDCl3) δ 172.3, 140.0, 138.8, 128.8, 128.6, 128.4, 128.1,
127.3, 126.4, 61.9, 60.3, 56.5, 54.6, 35.0, 22.6, 13.7; HRMS calcd
for C22H29NO3SNa (M + Na) 410.1765, found 410.1766.
afforded 0.101 g (79%) of colorless oil: [R]20 +45.0 (c 0.21,
D
CHCl3), [R]20 -43.0 (c 1.09, CHCl3) for the enantiomer of (-)-
D
1
7; IR (neat) 3279, 1733, 1161 cm-1; H NMR (CDCl3) δ 7.48 (d,
(RS,2S,3S)-(-)-Ethyl-2-methyl-3-(tert-butylsulfinylamino)pen-
tanoate (15d). In a 50 mL, dry, single-necked round-bottom flask
equipped with a magnetic stirring bar, rubber septum, and a H2
balloon were placed (-)-14d (0.05 g, 0.17 mmol) and rhodium
complex A (0.009 g, 0.013 mmol) in anhydrous DCM (5 mL). The
solution was evacuated and filled with H2, and this sequence was
repeated five times. The reaction mixture was stirred at rt for 48 h.
Preparative TLC (50% EtOAc/hexane) afforded 0.0255 g (55%)
J ) 8.0 Hz, 2H), 7.12 (m, 3H), 7.05 (d, J ) 8.4 Hz, 2H), 7.0 (m,
2H), 5.96 (d, J ) 8.8 Hz, 1H), 4.50 (dd, J ) 6.0, 8.4 Hz, 1H), 4.01
(q, J ) 7.2 Hz, 2H), 2.79 (quint, J ) 6.4 Hz, 1H), 2.31 (s, 3H),
1.13 (m, 6H); 13C NMR δ 174.9, 143.1, 139.4, 138.4, 129.5, 128.6,
127.7, 127.3, 126.9, 61.2, 60.5, 46.3, 21.7, 15.8, 14.3; HRMS calcd
for C19H22NO4S (M + H) 362.1426, found 362.1419.
(2R,3S)-(-)-2-Methyl-3-(4-methylphenylsulfonamido)-3-phenyl-
propanoic acid (8). In an oven-dried, 10 mL one-necked, round-
bottomed flask equipped with a magnetic stirring bar, reflux
condenser, and rubber septum were placed (-)-7 (0.0435 g, 0.120
mmol) and LiOH monohydrate (0.0435 g, 0.120 mmol) in THF (9
mL) and H2O (0.33 mL). The reaction mixture was refluxed for
16 h at 67 °C, cooled to rt, and concentrated. The residue was
diluted with DCM (10 mL), and 1 N HCl was added until the
solution reached pH >2. The solution was stirred for 10 min and
extracted with DCM (3 × 5 mL), and the combined organic phases
were washed with brine (4 mL), dried (MgSO4), and concentrated.
Preparative TLC (50% EtOAc/hexanes) afforded 0.0363 g (91%)
of a colorless oil: [R]20 -31.46 (c 0.06, CHCl3); IR (neat) 3280,
D
1732, 1462, cm-1; 1H NMR (CDCl3) δ 4.06 (m, 2H), 3.62 (d, J )
12 Hz, 1H), 3.29 (m, 1H), 2.69 (m, 1H), 1.72 (m, 1H), 1.26 (t, J
) 7.2 Hz, 3H) 1.23 (s, 9H), 1.19 (d, J ) 7.2 Hz, 3H), 0.99 (t, J )
7.6 Hz, 3H); 13C NMR (CDCl3) δ 174.9, 61.3, 60.4, 56.2, 43.4,
27.37, 22.7, 14.7, 14.2, 10.0; HRMS calcd for C12H26NO3S (M +
H) 264.1633, found 264.1613.
(RS,2S,3S)-(-)-Ethyl 2-Benzyl-3-(1,1-dimethylethylsulfinamido-
)pentanoate (15f). Preparative TLC (50% EtOAc/hexanes) afforded
77% of a colorless oil: [R]20 -27.7 (c 0.51, CHCl3); IR (neat)
D
1
3228, 1731, 1053 cm-1; H NMR (CDCl3) major isomer δ 7.19
of white solid: mp 131-133 °C; [lit15b mp 135-136 °C]; [R]20
(m, 5H), 4.00 (q, J ) 7.6 Hz, 2H), 3.66 (m, 1H), 3.23 (d, J ) 7.6
Hz, 1H), 2.96 (m, 2H), 2.85 (m, 1H), 1.77 (m, 1H), 1.62 (m, 1H),
1.20 (s, 9H), 1.10 (t, J ) 8.1 Hz, 3H), 0.97 (t, J ) 7.6 Hz, 3H);
13C NMR (CDCl3) δ 173.2, 139.2, 128.8, 128.5, 126.4, 60.4, 59.8,
56.2, 52.0, 34.1, 26.8, 22.9, 14.1, 10.4; HRMS calcd for
C18H29NO3SNa (M + Na) 362.1766, found 362.1761.
D
-23.6 (c 0.49, EtOAc), [lit15b [R]20D -25.6 (c 0.06, EtOAc), lit15a
[R]20 -28.1 (c 1.0, EtOAc)]; IR (neat) 3263, 1712, 1160 cm-1
;
D
1H NMR (CDCl3) δ 7.47 (m, 2H), 7.11 (m, 3H), 7.02 (m, 4H),
6.20 (d, J ) 9.2 Hz, 1H), 4.50 (dd, J ) 7.2, 8.8 Hz, 1H), 2.87
(quint, J ) 6.8 Hz, 1H), 2.29 (s, 3H), 1.17 (d, J ) 6.8 Hz, 3H);
13C NMR δ 178.6, 143.3, 138.9, 138.0, 129.5, 128.7, 127.9, 127.3,
127.1, 60.5, 46.1, 21.7, 15.7; HRMS calcd for C17H20NO4S (M +
H) 334.1113, found 334.1126. Spectral properties were consistent
with literature values.15
(2R,3S)-(-)-Ethyl 2-Methyl-3-(4-methylphenylsulfonamido)-3-
phenylpropanoate (7) from (+)-5. In an oven-dried, 10 mL one-
neck, round-bottomed flask equipped with a magnetic stirring bar,
rubber septum, and argon balloon was placed (+)-5 (0.168 g, 0.486
mmol) in DCM (18.0 mL). The solution was cooled to 0 °C,
m-CPBA (0.336 g, 1.458 mmol, 75 wt %) was added in one portion,
and the reaction mixture was warmed to rt, stirred for 1.5 h, and
quenched by addition of saturated Na2S2O3 solution (10 mL). The
solution was extracted with DCM (2 × 5 mL), and the combined
organic phases were washed with saturated NaHCO3 solution (2
× 5 mL) and brine (5 mL), dried (MgSO4), and concentrated. Flash
chromatography (50% EtOAc/hexanes) afforded 0.145 g (88%) of
a colorless oil: [R]20D -43.0 (c 1.09, CHCl3); IR (neat) 3279, 1733,
1161 cm-1; 1H NMR (CDCl3) δ 7.48 (d, J ) 8.0 Hz, 2H), 7.12 (m,
3H), 7.05 (d, J ) 8.4 Hz, 2H), 7.00 (m, 2H), 5.96 (d, J ) 8.8 Hz,
1H), 4.50 (dd, J ) 6.0, 8.4 Hz, 1H), 4.01 (q, J ) 7.2 Hz, 2H), 2.79
(quint, J ) 6.4 Hz, 1H), 2.31 (s, 3H), 1.13 (m, 6H); 13C NMR δ
174.9, 143.1, 139.4, 138.4, 129.5, 128.6, 127.7, 127.3, 126.9, 61.2,
60.5, 46.3, 21.7, 15.8, 14.3. Spectral properties were consistent with
literature values.25
(2S,3R)-(+)-Ethyl 2-Methyl-3-(4-methylphenylsulfonamido)-3-
phenylpropanoate, the Enantiomer of (-)-(7) from (RS,2S)-(-)-
15a. In an oven-dried, 50 mL one-necked, round-bottomed flask
equipped with a magnetic stirring bar, rubber septum, and argon
balloon was placed (-)-15a (0.110 g, 0.354 mmol) in anhydrous
MeOH (13 mL). The solution was cooled to 0 °C, and HCl (0.7
mL, 2.0 M in Et2O) was added dropwise, warmed to rt, stirred for
3 h, and quenched by addition of 1 N NaOH solution adjusting the
pH to 9. The solution was extracted with EtOAc (3 × 5 mL),
washed with brine (5 mL), dried (MgSO4), and concentrated. The
residue was placed in a 15 mL single-necked, round-bottomed flask
equipped with a magnetic stirring bar, rubber septum, and argon
(3R,4S)-(-)-3-Methyl-4-phenyl-1-tosylazetidin-2-one (9). In an
oven-dried, 10 mL one-necked, round-bottomed flask equipped with
a magnetic stirring bar, rubber septum, and argon balloon were
placed (-)-8 (0.0224 g, 0.067 mmol), DCC (0.017 mg, 0.0804
mmol), and 4-pyrrolidinopyridine (3.7 mg) in DCM (2.5 mL). The
reaction mixture was stirred for 16 h at rt, filtered through Celite,
and the filtrate was washed with water (3.0 mL), 5% aqueous HOAc
(3 mL), and water (3 mL). The organic phase was washed with
brine (3.5 mL), dried (MgSO4), and concentrated. Preparative TLC
(25% EtOAc/hexanes) afforded 0.0165 g (80%) of a white solid:
mp 133-135 °C [lit15a mp 134-135 °C; [R]20 -103 (c 0.58,
D
EtOAc), lit15a [R]20D -114 (c 1.05, EtOAc)]; IR (neat) 1794, 1361,
1
1168 cm-1; H NMR (CDCl3) δ 7.62 (dd, J ) 3.2, 6.4 Hz, 2H),
7.26 (m, 7H), 4.60 (d, J ) 3.2 Hz, 1H), 3.16 (m, 1H), 2.42 (s, 3H),
1.34 (d, J ) 7.6 Hz, 3H); 13C NMR δ 167.9, 145.4, 136.5, 136.1,
130.1, 129.3, 129.2, 127.8, 126.9, 65.4, 55.0, 22.0, 12.8; HRMS
calcd for C17H18NO3S (M + H) 316.1007, found 316.1013. Spectra
properties were consistent with literature values.15
Acknowledgment. We thank Professor Rodrigo Andrade of
Temple University for helpful suggestions. This work was
supported by a grant from the National Institutes of General
Medical Sciences (GM 57870) and Boehringer Ingelheim
Pharmaceuticals.
Supporting Information Available: Spectroscopic data for
all new compounds are provided. This material is available free
of charge via the Internet at http://pubs.acs.org.
(25) Campi, E. M.; Holmes, A.; Permutter, P.; Teo, C. C. Aust. J. Chem.
1995, 48, 1535.
JO9001504
J. Org. Chem. Vol. 74, No. 7, 2009 2803