Asymmetric synthesis of cyclic cis -β-Amino acid derivatives using sulfinimines and prochiral weinreb amide enolates

Article abstract of DOI:10.1021/jo100680b

Figure presented Cyclic cis-β-amino Weinreb amides, valuable building blocks for the asymmetric synthesis of cyclic β-amino acids derivatives, are readily prepared via ring-closing metathesis of sulfinimine-derived N-sulfinyl β-amino diene Weinreb amides.

Full text of DOI:10.1021/jo100680b

pubs.acs.org/joc
Asymmetric Synthesis of Cyclic cis-β-Amino Acid Derivatives Using
Sulfinimines and Prochiral Weinreb Amide Enolates
Franklin A. Davis* and Naresh Theddu
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122
fdavis@temple.edu
Received April 8, 2010
Cyclic cis-β-amino Weinreb amides, valuable building blocks for the asymmetric synthesis of cyclic
β-amino acids derivatives, are readily prepared via ring-closing metathesis of sulfinimine-derived
N-sulfinyl β-amino diene Weinreb amides. These unsaturated cyclic cis-β-amino Weinreb amides are
valuable building blocks for the asymmetric synthesis of cyclic β-amino acid derivatives.
Introduction
alcohols,5-7 and they undergo Wittig-type condensations to
give homoallylic amines.4,5,8,9 The intramolecular Mannich
cyclization of β-amino ketones with aldehydes is a parti-
cularly useful method for the asymmetric synthesis of stereo-
defined piperidones,10 indolizidines,11 tropinones,12 homo-
tropinones,13 and other alklaloids.14 Until recently there
were few methods available for the synthesis of enantiopure
β-amino ketones and aldehydes, and most of these were of
limited scope.15
In 2005 we introduced N-sulfinyl β-amino Weinreb
amides, which provided a general solution to the problem
of enantiopure β-amino ketone and aldehyde synthesis
(Figure 1).16 Despite the fact that these Weinreb amides have
an acidic NH proton, they react with lithium and Grignard
The importance of Weinreb amides,1 N-methoxy-N-methyl-
amides, as acylating agents in organometallic reactions is well
established.2 For example, Weinreb amides react with organo-
lithium and organomagesium reagents to give ketones, with
reducing agents LiAlH4 and DiBAL to give aldehydes, with
enolates to give β-ketoesters, and with phosphonates anions to
give β-ketophosphonates.2 Most often Weinreb amides are
prepared from an acid or acid derivative using N,O-dimethyl-
hydroxlamine, which is commercially available.2
Enantiopure β-amino carbonyl moieties are found as
structural units of natural products3 and are important chiral
building blocks for the synthesis of nitrogen-containing
bioactive molecules. They have been employed in the synthe-
sis of β-amino acids4 and in the synthesis of 1,3-amino
(8) For leading references, see: Ishimaru, K.; Kojima, T. J. Org. Chem.
2000, 65, 8395.
(9) Davis, F. A.; Song, M.; Augustine, A. J. Org. Chem. 2006, 71, 2779.
(10) For leading references, see: Davis, F. A.; Santhanaraman, M. J. Org.
Chem. 2006, 71, 4222.
(11) (a) Davis, F. A.; Yang, B. Org. Lett. 2003, 5, 5011. (b) Davis, F. A.;
Yang, B. J. Am. Chem. Soc. 2005, 127, 8398. (c) Davis, F. A.; Song, M.; Qiu,
H.; Chai, J. Org. Biomol. Chem. 2009, 7, 5067.
(12) Davis, F. A.; Theddu, N.; Gaspari, P. M. Org. Lett. 2009, 11, 1647.
(13) Davis, F. A.; Edupuganti, R. Org. Lett. 2010, 12, 848.
(14) (a) Schultz, A. G.; Dai, M. Tetrahedron Lett. 1999, 40, 645. (b) Chan,
C.; Zheng, S.; Zhou, B.; Guo, J.; Heid, R. M.; Wright, B. J. D.; Danishefsky,
S. J. Angew. Chem., Int. Ed. 2006, 45, 1749.
(1) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(2) For reviews, see: (a) Balaasubramaniam, S.; Aidhen, I. S. Synthesis
2008, 3707. (b) Singh, J.; Satyamurthi, N.; Aidhen, I. S. J. Prakt. Chem. 2000,
342, 340. (c) Mentzel, M.; Hoffmann, H. M. R. J. Prakt. Chem. 1997, 339,
517. (d) Sibi, M. P. Org. Prep. Proced. Int. 1993, 25, 15.
(3) (a) Davis, F. A.; Szewczyk, J. M. Tetrahedron Lett. 1998, 39, 5951. (b)
Seebach, D.; Kimmerlin, T.; Sebesta, R.; Campo, M. A.; Beck, A. K.
Tetrahedron 2004, 60, 7455.
(4) For recent reviews on the asymmetric synthesis of β-amino acids, see:
(a) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991. (b) Cole, D. C.
Tetrahedron 1994, 50, 9517.
(5) For a review, see: Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58, 5957.
(6) Jefford, C. W.; Wang, J. B. Tetrahedron Lett. 1993, 34, 2911.
(7) (a) Davis, F. A.; Prasad, K. R.; Nolt, M. B.; Wu, Y. Org. Lett. 2003, 5,
925. (b) Davis, F. A.; Gaspari, P. M.; Nolt, M. B.; Xu, P. J. Org. Chem. 2008,
73, 9619.
(15) For leading references, see: Davis, F. A.; Song, M. Org. Lett. 2007, 9,
2413.
(16) Davis, F. A.; Nolt, M. B.; Wu, Y.; Prasad, K. R.; Li, D.; Yang, B.;
Bowen, K.; Lee, S. H.; Eardley, J. H. J. Org. Chem. 2005, 70, 2184.
3814 J. Org. Chem. 2010, 75, 3814–3820
Published on Web 05/12/2010
DOI: 10.1021/jo100680b
r
2010 American Chemical Society

Davis and Theddu
JOCArticle
SCHEME 1
TABLE 1. Synthesis of R-Substituted Weinreb Amides at -78 °C
in THF
entry
5 (n)
base
6: yield (%)a (dr, syn:anti)b
1
2
3
4
5
6
5a (1)
KHMDS
NaHMDS
LiHMDS
LDA
LDA
LDA
6a: 92 (39:34:18:9)
6a: 90 (68:10:10:6)
6a: 90 (77:15:8:0)
6a: 89 (>99:1)
6b: 90 (>99:1)
6c: 90 (>99:1)
FIGURE 1. Synthesis of N-sulfinyl β-amino Weinreb amides and
ketones.
5b (2)
5c (3)
aCombined yields of inseparable isomers. bDetermined by 1H NMR
on the crude reaction mixture.
BnO(CH2)2, however, separable diastereoisomers were ob-
served only for the N-2,4,6-triisopropylphenyl N-sulfinyl
auxiliary (TIPP).11c,15 The best selectivity for the addition of
the lithium enolate of 2 to masked oxo sulfinimines was
observed for the p-tolyl N-sulfinyl auxiliary (R1 = p-tolyl).13
In each case the E-geometry for the enolate and a chairlike
transition state were evoked to explain the preference for the syn-
product.15,22 We describe here very high diastereoselectivities for
the addition of unsaturated prochiral Weinreb amide enolates to
an acrolein-derived sulfinimine. The resulting amino dienes were
employed in the asymmetric synthesis of five-, six-, and seven-
membered cyclic cis-β-amino acid derivatives.
FIGURE 2. Synthesis of R-substituted β-amino Weinreb amides
from Weinreb amide enolates.
reagents to give good yields of ketones and, on reduction
with DIBAL, aldehydes. The addition of Weinreb amide
enolates to sulfinimines (N-sulfinyl imines)17,18 was used for
the first time to prepare N-sulfinyl β-amino Weinreb ami-
des.19 The yields and diastereoselectivity were good to
excellent and dependent on the substrate (R1) and enolate
counterion. Potassium enolates and alkyl aldehyde derived
sulfinimines afforded the best selectivities (Figure 1).7,12,16
The current challenge is to prepare R-branched β-amino
Weinreb amides for applications in the synthesis of bio-
active nitrogen-containing compounds. For this reason we
have been exploring the addition of prochiral Weinreb amide
enolates to sulfinimines.7b,11,13,20,21 We found, for example,
that lithium Weinreb amide enolate 2, derived from N-methoxy-
N-methylpropylamide, adds to sulfinimine (S)-(þ)-1 to afford a
mixture of diastereoisomers with the syn-R-methyl β-amino
Weinreb amide 3 predominating (Figure 2).12,15 For R2 = alkyl,
Results and Discussion
The prochiral Weinreb amide enolate of N-methoxy-N-
methyl-4-pentenamide (5a, n = 1) was generated at -78 °C
by addition of 1.1 equiv of the appropriate base at -78 °C
(Scheme 1). After 2 h, 0.5 equiv of (S)-(þ)-N-(propylidene)-
p-toluenesulfinamide (4)23 was added to the preformed eno-
late, and TLC was used to monitor the reaction progress for
completion (typically l h) (Scheme 1). Products were isolated
by chromatography and are recorded in Table 1. Poor
selectivities were found for the enolate of 5a prepared using
the bases KHMDS, NaHMDS, and LiHMDS (Table 1,
entries 1-4). Significantly, only syn-R-(2-propenyl) β-amino
Weinreb amide (6) was obtained, in excellent yield, when
LDA was used to prepare the enolate (Table 1, entry 4).
Similar single diastereoisomer formation was observed with
this base and the Weinreb amide enolates prepared from
N-methoxy-N-methyl-5-hexenamide (5b) and N-methoxy-
N-methyl-6-heptenamide (5c) (Table 1, entries 5 and 6).
Cyclic β-Amino Acid Derivatives. Cyclic β-amino acids are
important building blocks for the synthesis of natural products
(17) Davis, F. A. J. Org. Chem. 2006, 71, 8993.
(18) For reviews on sulfinimines, see: (a) Morton, D.; Stockman, R. A.
Tetrahedron 2006, 62, 8869. (b) Senanayake, C. H.; Krishnamurthy, D.; Lu,
Z.-H.; Han, Z.; Gallou, I. Aldrichimica Acta 2005, 38, 93. (c) Zhou, P.; Chen,
B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8030.
(19) For the synthesis of N-sulfinyl β-amino ketones from methyl ketone
enolates, see: Davis, F. A.; Yang, B. Org. Lett. 2003, 5, 5011.
(20) For leading references to the addition of prochiral enolates to
sulfinimines see ref 15.
(21) For a related study, see: Ai, T.; Han, J.; Z-X., Chen; Li, G. Chem.
Biol. Drug Des. 2009, 73, 203.
(22) Glycine E-enolates add to sulfinimnes to give the syn product as the
major isomer. Davis, F. A.; Zhang, Y.; Qiu, H. Org. Lett. 2007, 9, 833.
(23) For reviews on cyclic β-amino acids, see: (a) Fulop, F. Chem. Rev.
2001, 101, 2181. (b) Miller, J. A.; Nguyen, S. T. Mini-Rev. Org. Chem. 2005,
2, 39.
J. Org. Chem. Vol. 75, No. 11, 2010 3815

Davis and Theddu
JOCArticle
SCHEME 2
FIGURE 3. Important cyclic β-amino acid derivatives.
and β-peptides.23 Peptides prepared with cyclic β-amino acids
often exhibit enhanced biostability and activity.24 Cispentacin
(7) is a naturally occurring, powerful antifungal antibiotic25
and is a constituent of amipurimycin, which is active against
Pyricularia oryzane, the organism responsible for rice blast
disease (Figure 3).26 The pharmaceutical Tilidine (8) is an
important opioid analgesic.27 Hydroxy-functionalized cyclic
β-amino esters have been explored as building blocks for the
synthesis of natural products and drug candidates.23,28,29
While a number of resolution and kinetic resolution proce-
dures have been devised for the synthesis of cyclic optically
active β-amino acids,23,30,31 there are surprisingly few methods
for their asymmetric synthesis, and most of these lack gene-
rality.23b Enantioselective routes to five- and six-membered
cyclic trans-β-amino acids include intramolecular self-conden-
sation routes,32 the addition of chiral nucleophiles to unsatu-
rated cyclic carboxylic acids,33 ring-closing metathesis,34 and
cross-metathesis leading to both cis- and trans-fluorinated
cyclic β-amino acids.35 Enantioselective hydrogenation of
cyclic β-(acylamino)acrylates affords five-, six-, and seven-
membered cyclic cis-β-amino acids that can be isomerized to
the trans isomers.36
It is well-known that ring-closing metathesis (RCM) is
sensitive to both the electronic and steric properties of the
alkene,37-39 as well as the substituents on nitrogen.34,37,40
However, our earlier studies on the synthesis of (þ)-4-amino-
cyclopentenone41 and (-)-agelastatin A42 demonstrated that
the N-sulfinyl group is compatible with RCM. Reaction of
N-sulfinyl β-amino diene Weinreb amides 6 with 2 mol % of
Grubbs II in DCM at rt for 16 h gave the corresponding
cyclic cis-β-amino Weinreb amides (SS,1R,2S)-(þ)-9 in mod-
erate to good yield (Scheme 2). For comparison the corre-
sponding N-tosly β-amino diene Weinreb amides (-)-10
were cyclized (Scheme 2). In each example there was a
noticeable improvement in the yields, which may reflect
poorer coordination of the catalyst to the N-tosyl group. Epi-
merization was not detected, and the syn relationship of the
two substituents was established on the basis of NOE studies
on the N-tosyl derivative of (þ)-11a. These results confirm
the syn orientation of the R-substituent in 6 and provide
additional support for our transition state model.15,22
(24) For leading references, see: Appella, D. H.; Christianson, L. A.;
Klein, D. A.; Richards, M. R.; Powell, D. R.; Gellman, S. M. J. Am. Chem.
Soc. 1999, 121, 7574.
(25) (a) Konishi, M.; Nishio, M.; Saitaoh, T.; Miyaki, T.; Oki, T.;
Kawaguchi, J. J. Antibiot. 1989, 42, 1749. (b) Oki, T.; Hirano, M.; Tomats,
K.; Numata, K.; Kamei, H. J. Antibiot. 1989, 42, 1756.
(26) (a) Rauter, A. P.; Fernandes, A. C.; Czernecki, S.; Valery, J.-M.
J. Org. Chem. 1996, 61, 3594. (b) Czernecki, S.; Franco, S.; Valery, J.-M.
J. Org. Chem. 1997, 62, 4845.
(27) Kleeman, A.; Engel, J. Pharmaceuatical Substances, 3rd ed.; Thieme:
Stuttgart, 1999; pp 1878-1879.
(28) For a review on hydroxylated cyclic β-amino acid derivatives, see:
Palko, M.; Kiss, L.; Fulop, F. Curr. Med. Chem. 2005, 12, 3063.
(29) (a) Benedek, G.; Palko, M.; Weber, E.; Martinek, T. A.; Forro, E.;
Fulop, F. Eur. J. Org. Chem. 2008, 3724. (b) Soengas, R. G.; Pampin, M. B.;
Estevez, J. C.; Estevez, R. J. Tetrahedron: Asymmetry 2005, 16, 205. (c)
Elliott, R. P.; Hui, A.; Fairbanks, A. J.; Nash, R. J.; Winchester, B. G.; Way,
G.; Smith, C.; Lamont, R. B.; Storer, R.; Fleet, G. W. J. Tetrahedron Lett.
1993, 34, 7949.
(30) For a review of resolution methods, see: Forro, E.; Fulop, F. Mini-
Rev. Org. Chem. 2004, 1, 93.
(31) Kinetic resolution see: Davies, S. G.; Durbin, M. J.; Hartman, S. J. S.;
Matsuno, A.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E.;
Toms, S. M. Tetrahedron: Asymmetry 2008, 19, 2870.
(32) (a) Enders, D.; Wiedemann, J. Liebigs Ann./Recueil. 1977, 699. (b)
O’Brein, P.; Porter, D. W.; Smith, N. M. Synlett 2000, 1336. (c) Schenkel,
L. B.; Ellman, J. A. Org. Lett. 2004, 6, 3621.
(33) (a) Davies, S. G.; Ichihara, O.; Walters, I . A. S. Synlett 1993, 461. (b)
Price, D. A. Synlett 1999, 1919.
(34) Chippindale, A. M.; Davies, S. G.; Iwamoto, K.; Parkin, R. M.;
Smethurst, C. A. P.; Smith, A. D.; Rodriguez-Solla, H. Tetrahedron 2003, 59,
3253.
The availability of five-, six-, and seven-membered unsatu-
rated cyclic cis-β-amino Weinreb amides 9 and 11 (Scheme 2)
provide numerous opportunities for functionalization, afford-
ing new cyclic β-amino acid building blocks. These possibilities
(35) Fuestero, S.; Sanchez-Rosello, M.; Acena, J. L.; Fernandez, B.;
Asensio, A.; Sanz-Cervera, J. F.; del Pozo, C. J. Org. Chem. 2009, 74, 3414.
(36) Tang, W.; Wu, S.; Zhang, X. J. Am. Chem. Soc. 2003, 125, 9570.
(37) For reviews and leading references on ring-closing metathesis, see:
(a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (b) Hanessian, S.;
Margarita, R.; Hall, A.; Johnstone, S.; Tremblay, M.; Parlanti, L. J. Am.
Chem. Soc. 2002, 124, 13342. (c) Felpin, F.-X.; Lebreton, J. Eur. J. Org.
Chem. 2003, 3693. (d) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs,
R. H. J. Am. Chem. Soc. 2003, 125, 11360.
(38) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am.
Chem. Soc. 2000, 122, 3783.
(39) Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310.
(40) Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc. 1996,
118, 9606.
(41) Davis, F. A.; Wu, Y. Org. Lett. 2004, 6, 1269.
(42) (a) Davis, F. A.; Deng, J. Org. Lett. 2005, 7, 621. (b) Davis, F. A.;
Zhang, J.; Zhang, Y.; Qiu, H. Synth. Commun. 2009, 39, 1914.
3816 J. Org. Chem. Vol. 75, No. 11, 2010

Davis and Theddu
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SCHEME 3
decomposition. However, hydrolysis of the saturated deri-
vative (-)-14 (refluxing KOH/THF) afforded the desired
acid (-)-16 in 80% yield without epimerization. Despite the
enhanced acidity of the N-tosyl proton in (þ)-11a, treatment
with 3-5 equiv of a Grignard reagent (MeMgBr and PhMg-
Br) readily afforded the corresponding ketones (þ)-17 (R =
Me, 91%) and (-)-18 (R = Ph, 89%) in excellent yield
(Scheme 4). By analogy similar functionalization of the
6- and 7-membered cyclic β-amino Weinreb amides (þ)-
11b and (þ)-11c can be envisioned. Removal of the N-tosyl
group can be easily accomplished without epimerization, via
reduction with sodium naphthalide, Mg/MeOH, Na(Hg),
and cleavage with HBr in HOAc.44 In our studies we
have found that Na/NH3 (liq) is particularly effective for
removal of the N-p-toluenesulfonyl protecting group.44g
These reductive methods are tolerant of carbonyl and ole-
finic functionalities.
SCHEME 4
In summary, new, general methodology has been intro-
duced for the asymmetric synthesis of functionalized cyclic
five-, six-, and seven-membered cis-β-amino Weinreb amides
(þ)-7, valuable building blocks for the synthesis of cyclic
β-amino acid derivatives. This protocol involves RCM of
N-sulfinyl β-amino diene Weinreb amides (þ)-6 or the N-
tosyl derivatives (þ)-10, which are readily available via the
highly diastereoselective addition of unsaturated prochiral
Weinreb amide enolates to sulfinimines.
Experimental Section
(S)-(þ)-N-(Propylidene)-p-toluenesulfinamide (4),42a N-methoxy-
N-methyl-4-pentenamide (5a),45 and N-methoxy-N-methyl-4-
hexenamide (5b)45 were prepared according to literature procedures.
N-Methoxy-N-methyl-6-heptenamide (5c). This material was
prepared using the procedure of Guillaume and co-workers
using a modified procedure.45 In an oven-dried 100 mL one-
neck round-bottomed flask equipped with a magnetic stirring
bar, rubber septum, and argon inlet was placed 6-heptenoic acid
(0.38 g, 2.95 mmol) in dichloromethane (30 mL). N-Methyl-
piperidine (2.93 g, 29.52 mmol) was added, the solution was
stirred for 10 min at rt, and trimethylacetyl chloride (0.53 g,
4.43 mmol) was added dropwise via syringe. The yellow-colored
solution was stirred at 0 °C for 2 h, N,O-dimethylhydroxylamine
hydrochloride (0.52 g, 5.31 mmol) was added, and the reaction
mixture was stirred at rt for 16 h. At this time the reaction
mixture was diluted with 1.0 M aqueous hydrochloric acid
(20 mL). The organic phase was washed with satd NaHCO3
and brine, dried (MgSO4), and concentrated. Chromatography
(50% EtOAc/hexanes) gave 0.50 g (99%) of a clear oil: 1H NMR
(CDCl3) δ 1.43 (m, 2H), 1.64 (m, 2H), 2.06 (m, 2H), 2.41 (t,
J = 7.96 Hz, 2H), 3.16 (s, 3H), 3.67 (s, 3H), 4.95 (m, 2H), 5.79
(m, 1H); 13C NMR (CDCl3) δ 24.1, 28.6, 31.7, 32.1, 33.5, 61.2,
114.5, 138.6, 174.6; IR (film) 3077, 1642 cm-1. HRMS calcd for
C9H18NO2 (M þ H) 172.1332, found 172.1335.
are illustrated for the five-membered β-amino Weinreb amide
(þ)-9a. Removal of the N-sulfinyl group was accomplished by
treating (þ)-9a with TFA/MeOH giving the amine (1R,
2S)-(þ)-12 in quantitative yield and was isolated as the
hydrochloride salt (Scheme 3). Treatment of (þ)-9a with
7 equiv of MeMgBr afforded the methyl ketone (SS,1R,2S)-(þ)-
13 in 89% yield. However, attempts to obtain the acid by
refluxing (þ)-9a with KOH in THF for 48 h resulted in de-
composition, and hydrogenation (H2/Pd-C) failed to reduce
the double bond, resulting in recovery of (þ)-9a (>90%).
To circumvent these problems, these transformations were
carried out using the cyclic N-tosyl derivative (1R,2S)-(þ)-11a
(Scheme 4).
Hydrogenation (Pd-C/H2) of (þ)-11a gave the saturated
cyclic β-amino Weinreb amide (-)-14 in quantitative yield
(Scheme 4). Dihydroxylation of (þ)-11a with OsO4/TME-
DA for 4 h gave the dihydroxy compound (-)-15 in 85% as a
single isomer. The stereochemistry was determined by NOE
studies and is consistent with hydroxylation from the more
hindered face of the cyclopentene ring directed by hydrogen
bonding.43 All attempts to hydrolyze the amide group in (þ)-
11a (refluxing KOH/THF) again failed and resulted in
(Ss,3S,2R)-(þ)-N-(p-Toluenesulfinyl)-3-amino-N-methoxy-
N-methyl-2-(2-propenyl)-pent-4-ene-amide (6a). In an oven-
dried 50 mL one-neck round-bottomed flask equipped with a
magnetic stirring bar, rubber septum, and argon inlet was placed
5a (0.19 g, 1.34 mmol) in THF (3.0 mL), the solution was cooled
(44) (a) (Naphthalene-Na) Closson, W. D.; Ji, S.; Schulenberg, S. J. Am.
Chem. Soc. 1970, 92, 650. (b) Na(Hg) Somfai, P.; Ahman, J. Tetrahedron Lett.
1992, 33, 3791. (c) (HOAc-HBr) Roemmele, R. C.; Rapoport, H. J. Org. Chem.
1988, 53, 2367. (d) (SmI2) Vedejs, E.; Lin, S. J. Org. Chem. 1994, 59, 1602. (e)
(Na-liq NH3) Magnus, P.; Coldham, I. J. Am. Chem. Soc. 1991, 113, 672. (g)
Davis, F. A.; Ramachandar, T.; Liu, H. Org. Lett. 2004, 6, 3393. (f) (MeOH-Mg)
Kumar, V.; Ramesh, N. G. Tetrahedron 2006, 62.
(43) Donohoe, T. J.; Mitchell, L.; Waring, M. J.; Helliwell, M.; Bell, A.;
Newcombe, N. J. Org. Biomol. Chem. 2003, 1, 2173.
(45) Guillaume, C.; Christophe, M.; Janine, C. Synlett 2007, 19, 2983.
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Davis and Theddu
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to -78 °C, LDA (1.97 mL, 1.475 mmol, 0.75 M solution in THF)
was added via syringe, and the reaction mixture was stirred for
2 h at this temperature. At this time a solution of (S)-(þ)-4 (0.13
g, 0.67 mmol) in THF (4.0 mL) was added via syringe, and the
reaction was monitored for completion by TLC (typically less
than 1 h). The reaction mixture was quenched by addition of
satd NH4Cl (5 mL) at -78 °C, warmed to rt, and extracted with
EtOAc (2 ꢀ 30 mL). The combined organic phases were washed
with brine (2 ꢀ 30 mL), dried (MgSO4), and concentrated.
Chromatography (50% EtOAc/hexanes) gave 0.20 g (89%) of
a colorless oil as a single isomer: [R]20D þ149.60 (c 0.63, CHCl3);
1H NMR (CDCl3) δ 2.29 (m, 1H), 2.40 (s, 3H), 2.42 (m, 1H),
3.12 (s, 3H), 3.17 (m, 1H), 3.63 (s, 3H), 4.11 (m, 1H), 4.73 (d, J =
3.7 Hz, 1H), 5.03 (m, 2H), 5.35 (m, 2H), 5.67 (m, 1H), 5.99 (m,
1H), 7.27 (d, J = 8.05 Hz, 2H), 7.56 (d, J = 8.2 Hz, 2H); 13C
NMR (CDCl3) δ 21.3, 32.0, 45.2, 58.4, 61.5, 117.2, 119.1, 125.4,
129.4, 135.3, 135.9, 141.2, 142.3, 173.7; IR (film) 3233, 1639
cm-1. HRMS calcd for C17H25N2O3S (M þ H) 337.1580, found
337.1582.
J = 2.0 Hz, J = 8.4 Hz, 2H); 13C NMR (CDCl3) δ 21.5, 27.2,
31.2, 32.0, 44.9, 57.9, 61.5, 115.3, 117.5, 127.3, 129.4, 135.3, 137.4,
137.5, 143.2, 173.8; IR(film) 3265, 1643, 1598 cm-1. HRMScalcd
for C18H27N2O4S (M þ H) 367.1686, found 367.1687.
(3S,2R)-(-)-N-(p-Toluenesulfonyl)-N-methoxy-N-methyl-3-
amino-2-(pent-4-enyl)-pent-4-enamide (10c). Chromatography
(50% EtOAc/hexanes) gave 0.075 g (91%) of a white solid,
mp 111-112 °C: [R]20 -10.08 (c 1.14, CHCl3); 1H NMR
D
(CDCl3) δ 1.31 (m, 1H), 1.47 (m, 1H), 1.60 (m, 1H), 1.98 (q,
J = 7.2 Hz, 2H), 2.42 (s, 3H), 3.06 (m, 1H), 3.08 (s, 3H), 3.65 (s,
3H), 3.84 (q, J = 7.2 Hz, 1H), 4.95 (m, 4H), 5.10 (d, J = 7.2 Hz,
1H), 5.76 (m, 2H), 7.25 (bd, J = 8.4 Hz, 2H), 7.70 (td, J = 2.0
Hz, J = 8.4 Hz, 2H); 13C NMR (CDCl3) δ 21.5, 26.6, 27.8, 31.9,
33.6, 45.6, 58.0, 61.5, 114.8, 117.4, 127.3, 129.4, 135.3, 137.4,
138.2, 143.2, 174.1; IR (film) 3265, 1643, 1598 cm-1. HRMS
calcd for C19H29N2O4S (M þ H) 381.1843, found 381.1848.
(SS,1R,2S)-(þ)-N-Methoxy-N-methyl-2-(N-p-toluenesulfinyl-
amino)-cyclopent-3-enyl Amide (9a) (typical procedure). In an
oven-dried 100 mL one-neck round-bottomed flask equipped
with a magnetic stirring bar, rubber septum, and argon inlet was
placed (þ)-6a (0.15 g, 0.43 mmol) in DCM (40 mL), and a
solution of Grubb’s second generation catalyst (0.02 g, 0.02
mmol) in DCM (5 mL) was added via cannula. The reaction
mixture was stirred for 20 h at rt and concentrated. Chromato-
graphy (60% EtOAc/hexanes) gave 0.11 g (80%) of a colorless
oil: [R]20D þ209.03 (c 1.13, CHCl3); 1H NMR (CDCl3) δ 2.37 (s,
3H), 2.44 (m, 1H), 2.82 (m, 1H), 3.18 (s, 3H), 3.56 (s, 3H), 3.62
(m, 1H), 4.50 (m, 1H), 4.83 (d, J = 10.4 Hz, 1H), 5.85 (m, 2H),
7.24 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H); 13C NMR
(CDCl3) δ 21.2, 32.2, 34.8, 42.5, 60.8, 61.3, 126.0, 129.4, 132.2,
(Ss,3S,2R)-(þ)-N-(p-Toluenesulfinyl)-N-methoxy-N-methyl-
3-amino-2-(but-3-enyl)-pent-4-enamide(6b). [R]20
þ114.84
D
(c 1.26, CHCl3); 1H NMR (CDCl3) δ 1.96 (m, 4H), 2.36 (s,
3H), 3.06 (s, 3H), 3.10 (m, 1H), 3.60 (s, 3H), 4.04 (m, 1H), 4.75
(d, J = 3.8 Hz, 1H), 4.96 (m, 2H), 5.30 (m, 2H), 5.69 (m, 1H),
5.96 (m, 1H), 7.24 (m, 2H), 7.53 (m, 2H); 13C NMR (CDCl3) δ
21.2, 26.6, 31.3, 32.0, 44.5, 58.3, 61.4, 115.2, 118.8, 125.4, 129.4,
136.1, 137.6, 141.1, 142.2, 174.1; IR (film) 3223, 3077, 1642
cm-1. HRMS calcd for C18H27N2O3S (M þ H) 351.1737, found
351.1741.
(Ss,3S,2R)-(þ)-N-(p-Toluenesulfinyl)-N-methoxy-N-methyl-
3-amino-2-(pent-4-enyl)-pent-4-enamide (6c). [R]20 þ131.62
132.3, 140.9, 141.6, 173.6; IR (film) 3223, 1642, 1610 cm-1
.
D
1
(c 0.68, CHCl3); H NMR (CDCl3) δ 1.71 (m, 3H), 2.05 (m,
HRMS calcd for C15H21N2O3S (M þ H) 309.1273, found
3H), 2.40 (s, 3H), 2.42 (m, 1H), 3.09 (m, 1H), 3.13 (s, 3H), 3.65 (s,
3H), 4.72 (d, J = 3.6 Hz, 1H), 4.94 (m, 2H), 5.35 (m, 2H), 5.76
(m, 1H), 6.01 (m, 1H), 7.28 (m, 2H), 7.57 (m, 2H); 13C NMR
(CDCl3) δ 21.3, 26.8, 27.2, 32.1, 33.6, 45.2, 58.5, 61.5, 114.7,
118.9, 125.4, 129.4, 136.2, 138.2, 141.2, 142.3, 174.4; IR (film)
3223, 3077, 1642 cm-1. HRMS calcd for C19H29N2O3S (M þ H)
365.1899, found 365.1899.
309.1275.
(SS,1R,2S)-(þ)-N-Methoxy-N-methyl-2-(N-p-toluenesulfinyl-
amino)-cyclohex-3-enyl Amide (9b). Chromatography (60% Et-
OAc/hexanes) gave 0.053 g (68%) of a colorless oil: [R]20D þ236.75
(c 1.78, CHCl3); 1H NMR (CDCl3) δ 1.72 (m, 2H), 1.97 (m, 3H),
2.33 (s, 3H), 3.06 (s, 3H), 3.12 (m, 1H), 3.55 (s, 3H), 4.03 (m, 1H),
4.93 (d, J = 8.8 Hz, 1H), 5.84 (m, 2H), 7.20 (m, 2H), 7.52 (m, 2H);
13C NMR (CDCl3) δ 21.3, 22.0, 23.1, 27.6, 31.9, 41.6, 50.6, 61.4,
126.0, 129.1, 129.2, 129.4, 140.9, 142.1, 173.5; IR (film) 3223, 1642,
1610 cm-1. HRMS calcd for C16H23N2O3S (M þ H) 323.1424,
found 323.1422.
(SS,1R,2S)-(þ)-N-Methoxy-N-methyl-2-(N-p-toluenesulfinyl-
amino)-cyclohept-3-enyl Amide (9c). Chromatography (60% EtO-
Ac/hexanes) gave 0.050 g (49%) of a colorless oil: [R]20D þ111.28
(c 2.66, CHCl3); 1H NMR (CDCl3) δ 1.52 (m, 1H), 1.73 (m, 2H),
2.13 (m, 2H), 2.45 (m, 1H), 2.32 (s, 3H), 3.03 (s, 3H), 3.19 (m, 1H),
3.61 (s, 3H), 4.16 (m, 1H), 5.14 (d, J = 5.6 Hz, 1H), 5.91 (m, 2H),
7.20 (m, 2H), 7.51 (m, 2H); 13C NMR (CDCl3) δ 21.2, 24.8, 27.9,
28.5, 31.8, 44.5, 53.8, 61.5, 125.4, 129.4, 130.7, 134.4, 140.9, 142.7,
175.3; IR (film) 3223, 1642, 1590 cm-1. HRMS calcd for
C17H25N2O3S (M þ H) 337.1580, found 337.1583.
(3S,2R)-(-)-N-(p-Toluenesulfonyl)-3-amino-N-methoxy-N-
methyl-2-(2-propenyl)-pent-4-ene-amide (10a) (typical procedure).
Inanoven-dried25mLone-neckround-bottomedflaskequipped
with a magnetic stirring bar, rubber septum, and argon inlet was
placed (þ)-6a (0.067 g, 0.2 mmol) in DCM (5 mL), m-chloroper-
oxybenzoic acid (0.052 g, 0.3 mmol) in DCM (3 mL) was slowly
added via syringe, and the solution was stirred for 1 h at rt. At this
time the reaction mixture was quenched by addition of satd
sodium bisulfite (3 mL) and stirred for 10 min. The phases were
separated, the aqueous phase was extracted with DCM (2 ꢀ
5 mL), and the combined organic phases were washed with
brine, dried (MgSO4), and concentrated. Chromatography
(50% EtOAc/hexanes) afforded 0.065 g (92%) of a white solid,
mp 84-85 °C: [R]20D -13.23 (c 1.31, CHCl3); 1H NMR (CDCl3)
δ 2.27 (m, 1H), 2.35 (m, 1H), 2.40 (s, 3H), 3.08 (s, 3H), 3.17 (m,
1H), 3.65 (s, 3H), 3.88 (q, J = 7.2 Hz, 1H), 4.98 (m, 4H), 5.11 (d,
J = 7.6 Hz, 1H), 5.68 (m, 1H), 5.78 (m, 1H), 7.27 (bd, J = 7.8 Hz,
2H), 7.70 (td, J = 2.0 Hz, J = 8.4 Hz, 2H); 13C NMR (CDCl3)
δ 21.5, 31.9, 32.7, 45.6, 57.8, 61.6, 117.3, 117.7, 127.3, 129.4,
(1R,2S)-(þ)-N-Methoxy-N-methyl-2-(N-p-toluenesulfonyl-
amino)-cyclopent-3-enyl Amide (11a). In an oven-dried, 25 mL
round-bottomed one-neck flask equipped with a magnetic stirring
bar, rubber septum, and argon inlet was placed (-)-10a (0.03 g,
0.085 mmol) in DCM (10 mL). A solution of Grubbs second gene-
ration catalyst (0.004 g, 0.004 mmol) in DCM (1 mL) was added via
syringe, and the solution was stirred for 16 h at rt, and concentrated.
Chromatography (60% EtOAc/hexanes) gave 0.025 g (90%) of a
white solid, mp 129-130 °C: [R]20D þ75.41 (c 0.54, CHCl3); 1H
NMR (CDCl3) δ 2.41 (s, 3H), 2.46 (m, 1H), 2.68 (m, 1H), 3.10 (s,
3H), 3.61 (s, 3H), 3.72 (m, 1H), 4.67 (m, 1H), 5.30 (m, 1H), 5.45
(d, J = 10.15 Hz, 1H), 5.80 (m, 1H), 7.27 (bd, J = 8.0 Hz, 2H),
7.72 (td, J = 1.9 Hz, J = 8.3 Hz, 2H); 13C NMR (CDCl3) δ 21.5,
32.0, 35.3, 40.8, 60.2, 61.5, 127.0, 129.5, 130.0, 132.8, 138.4,
143.1, 173.3; IR (film) 3265, 1643, 1598 cm-1. HRMS calcd for
134.8, 134.9, 137.4, 143.2, 173.4; IR (film) 3233, 1639 cm-1
.
HRMS calcd for C17H25N2O4S (M þ H) 353.1530, found
353.1531.
(3S,2R)-(-)-N-(p-Toluenesulfonyl)-N-methoxy-N-methyl-3-
amino-2-(but-3-enyl)-pent-4-enamide (10b). Chromatography
(50% EtOAc acetate/hexanes) gave 0.078 g (89%) of a white
solid, mp 84-85: [R]20 -12.89 (c 1.21, CHCl3); 1H NMR
D
(CDCl3) δ 1.57 (m, 1H), 1.73 (m, 1H), 1.98 (m, 2H), 2.40 (s,
3H), 3.07 (s, 3H), 3.11 (m, 1H), 3.65 (s, 3H), 3.86 (m, 1H), 4.95(m,
4H), 5.09 (d, J = 7.6 Hz, 1H), 5.75 (m, 2H), 7.25(m, 2H), 7.70 (td,
3818 J. Org. Chem. Vol. 75, No. 11, 2010

Davis and Theddu
JOCArticle
C15H21N2O4S (M þ H) 325.1222, found 325.1217. NOE: Upon
irradiation of N-OCH3 at δ 3.61, a positive NOE was observed on
the Ar-CH3 atδ 2.41; uponirradiation of the C-5 protonat δ 2.68,
a positive NOEwas observedonthe Ar-CH3 at δ2.41, confirming
a cis relationship between the C-1 proton and C-2 proton.
(1R,2S)-(þ)-N-Methoxy-N-methyl-2-(N-p-toluenesulfonyl-
amino)-cyclohex-3-enyl Amide (11b). Chromatography (60%
EtOAc/hexanes) gave 0.036 g (85%) of a white solid, mp 149-
150 °C: [R]20D þ54.12 (c 1.27, CHCl3); 1H NMR (CDCl3) δ 1.77
(m, 1H), 1.96 (m, 3H), 2.40 (s, 3H), 3.06 (s, 3H), 3.14 (m, 1H),
3.59 (s, 3H), 4.07 (m, 1H), 5.40 (m, 2H), 5.72 (m, 1H), 7.27 (bd,
J = 8.0 Hz, 2H), 7.73 (td, J = 2.0 Hz, J = 8.4 Hz, 2H); 13C
NMR (CDCl3) δ 21.4, 22.0, 22.8, 31.8, 40.5, 49.2, 61.4, 127.0,
129.2, 138.3, 143.0, 173.0; IR (film) 3265, 3028, 2922, 1643, 1598
cm-1. HRMS calcd for C16H23N2O4S (M þ H) 339.1373, found
339.1377.
IR (film) 3210, 3055, 1709 cm-1. HRMS calcd for C14H18NO2S
(M þ H) 264.1058, found 264.1053.
(1R,2S)-(-)-N-Methoxy-N-methyl-2-(N-p-toluenesulfonyl-
amino)-cyclopentyl Amide (14). In an oven-dried 25 mL one-
neck round-bottomed flask equipped with a magnetic stirring
bar, rubber septum, and argon inlet was placed (þ)-11a (0.035 g,
0.108 mmol) in ethanol (10 mL). Palladium (0.02 g, 20%
palladium on carbon) was added, and the reaction mixture was
stirred for 16 h at rt under hydrogen atmosphere (balloon). The
solution was filtered through Celite, and the filtrate was con-
centrated. Chromatography (60% EtOAc/hexanes) gave 0.035 g
(100%) of a white solid, mp 94-95 °C: [R]20 -11.41 (c 0.78,
D
CHCl3); 1H NMR (CDCl3) δ 1.44 (m, 1H), 1.75 (m, 5H), 2.40 (s,
3H), 3.08 (s, 3H), 3.23 (m, 1H), 3.54 (s, 3H), 3.76 (m, 1H), 5.89
(d, J = 8.4 Hz, 1H), 7.27 (m, 2H), 7.73 (m, 2H); 13C NMR
(CDCl3) δ 21.5, 22.1, 28.5, 31.8, 33.3, 41.9, 56.5, 61.4, 127.1,
129.5, 138.1, 142.9, 174.8; IR (film) 3258, 1643 cm-1. HRMS
calcd for C15H23N2O4S (M þ H) 327.1373, found 327.1374.
(1R,2R,3R,4S)-(-)-3,4-Dihydroxy-N-methoxy-N-methyl-2-
(tosylamino)cyclopentane-carboxamide (15). In an oven-dried
25 mL one-neck round-bottomed flask equipped with a mag-
netic stirring bar, rubber septum, and argon inlet was placed
(þ)-11a (0.013 g, 0.04 mmol) in DCM (4.0 mL), and TMEDA
(0.037 mL, 0.246 mmol) was slowly added at -78 °C via syringe.
After stirring for 5 min, OsO4 (0.7 mL, 0.044 mmol, 0.065 M
solution in DCM) was added via syringe, and the reaction
mixture was stirred at -78 °C for 4 h and concentrated. The
residue was dissolved in THF (4 mL), satd sodium sulfite
solution (4 mL) was added, and the reaction mixture was reflux-
ed for 2 h and filtered through Celite. Chromatography (EtOAc)
gave 0.012 g (85%) of a clear oil: [R]20D -20.0 (c 0.41, CHCl3);
1H NMR (CD3OD) δ 1.85 (M, 1H), 2.01 (M, 1H), 2.41 (S, 3H),
3.05 (S, 3H), 3.49 (S, 3H), 3.58 (m, 1H), 3.84 (m, 1H), 3.92 (m,
1H), 4.05 (m, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.05 Hz,
2H); 13C NMR (CDCl3) δ 21.5, 31.8, 33.8, 37.2, 58.9, 61.4, 69.9,
77.9, 127.2, 129.6, 137.4, 143.4, 174.5; IR (film) 3350, 2950, 1650
cm-1. HRMS calcd for C15H23N2O6S (M þ H) 359.1277, found
359.1266. NOE: Upon irradiation of the C-2 proton at δ 3.84, a
positive NOE was observed at the C-4 proton at δ 4.05,
confirming the cis relationship at C-2 proton, the C-3 proton,
and the C-4 proton.
(1R,2S)-(-)-N-Methoxy-N-methyl-2-(N-p-toluenesulfonyl-
amino)-cyclohept-3-enyl Amide (11c). Chromatography (60%
EtOAc/hexanes) gave 0.028 g (85%) of a white solid, mp
91-92 °C: [R]20D -39.52 (c 1.45, CHCl3); 1H NMR (CDCl3) δ
1.58 (m, 2H), 1.88 (m, 1H), 2.10 (m, 3H), 2.42 (s, 3H), 3.12 (s,
3H), 3.27 (m, 1H), 3.66 (s, 3H), 4.14 (m, 1H), 5.40 (m, 1H), 5.57
(m, 2H), 7.28 (bd, J = 7.6 Hz, 2H), 7.74 (td, J = 2.0 Hz, J = 8.4
Hz, 2H); 13C NMR (CDCl3) δ 21.5, 23.2, 28.3, 28.7, 31.9, 46.0,
53.4, 61.5, 127.2, 129.5, 130.2, 131.2, 137.7, 143.1, 174.2; IR
(film) 3265, 3028, 2922, 1643, 1598 cm-1. HRMS calcd for
C17H25N2O4S (M þ H) 353.1530, found 353.1535.
(1R,2S)-(þ)-2-Amino-N-methoxy-N-methylcyclopent-3-ene-
carboxamide Hydrochloride (12). In an oven-dried 25 mL one-
neck round-bottomed flask equipped with a magnetic stirring
bar, rubber septum, and argon inlet was placed (þ)-9a (0.110 g,
0.356 mmol) in MeOH (10.0 mL). Trifluoroacetic acid (0.275
mL, 3.566 mmol) was added at 0 °C via syringe, and the reaction
was monitored for completion by TLC (typically 2 h). At this
time the reaction mixture was concentrated, the residue was
dissolved in 10% aqueous hydrochloric acid (10 mL), and the
aqueous phase was extracted with dichloromethane (3 ꢀ 10
mL). The aqueous phase was freeze-dried to give 0.073 g (99%)
of a solid, mp 84-85 °C: [R]20 þ54.61 (c 0.26, MeOH); H
1
D
NMR (D2O) δ (italics denote values for the rotamer) 2.78 (m,
2H, same for both rotamers), 2.99 (s, 3H), 3.25 (s, 3H), 3.55 (q,
J = 8.4 Hz, 1H), 3.81 (s, 3H), 3.89 (s, 3H), 3.91 (q, J = 8.4 Hz,
1H), 4.48 (m, 1H, same for both rotamers), 5.84 (m, 1H, same for
both rotamers), 6.30 (m, 1H, same for both rotamers); 13C NMR
(D2O) δ 31.8 (34.8), 34.1 (34.5), 39.8 (43.6), 55.8 (56.8), 61.1
(61.7), 125.6 (125.8), 138.6 (138.7), 172.5 (175.5); IR (film) 3400,
1660 cm-1. HRMS calcd for C8H15N2O2 (M) 171.1134, found
171.1130.
(1R,2S)-(-)-2-(N-p-Toluenesulfonylamino)cyclopentanoic Acid
(16). In an oven-dried, 25 mL one-neck round-bottomed flask
equipped with a magnetic stirring bar, and rubber septum was
placed the (-)-14 (0.015 g, 0.046 mmol) in ethanol (2.0 mL).
Potassium hydroxide solution (2.0 mL, 2.0 M aqueous solution)
was added, and the solution was refluxed for 48 h. At this time conc
HCl was added until pH 2 was reached, and the solution was
extracted with EtOAc (4 ꢀ 10 mL). The combined organic phases
were washed with brine, dried (MgSO4), and concentrated.
Chromatography (EtOAc) afforded 0.010 g (80%) of a white
solid, mp 104-105 °C: [R]20D -28.73 (c 0.55, CHCl3); 1H NMR
(CDCl3) δ 1.45 (m, 1H), 1.68 (m, 3H), 1.95 (m, 2H), 2.45 (s, 3H),
2.91 (m, 1H), 3.78 (m, 1H), 6.30 (d, J = 8.8 Hz, 1H), 7.30 (m, 2H),
7.75 (td, J = 1.6 Hz, J = 8.4 Hz, 2H); 13C NMR (CDCl3) δ 21.5,
21.7, 27.8, 31.6, 46.2, 56.2, 127.0, 129.7, 137.5, 143.5, 178.1; IR
(film) 3258, 1707 cm-1. HRMS calcd for C13H18NO4S (M þ H)
284.0951, found 284.0944.
(1R,2S)-(-)-2-(N-p-Toluenesulfonylamino)-cyclopent-3-enyl
Phenyl Ketone (18). In an oven-dried 25 mL one-neck round-
bottomed flask equipped with a magnetic stirring bar, rubber
septum, and argon inlet was placed (þ)-11a (0.017 g, 0.054
mmol) in THF (5.0 mL). Phenylmagnesium chloride (0.08 mL,
0.161 mmol, 2.0 M solution in THF) was added to the solution
via syringe at -15 °C, and the reaction progress was monitored
by TLC (typically 2 h). At this time the reaction mixture was
quenched by addition of satd NH4Cl (2.0 mL) solution, diluted
with water (5 mL), extracted with EtOAc (3 ꢀ 10 mL), dried
1-(SS,1R,2S)-2-(N-p-Toluenesulfinylamino)cyclopent-3-enyl)-
ethanone (13). In an oven-dried 25 mL one-neck round-
bottomed flask equipped with a magnetic stirring bar, rubber
septum, and argon inlet was placed (þ)-9a (0.063 g, 0.204 mmol)
in THF (5.0 mL), and the solution was cooled to -15 °C.
Methylmagnesium bromide (0.5 mL, 1.5 mmol, 3.0 M solution
in THF) was added slowly via syringe at -15 °C, and the reaction
mixture was monitored by TLC for completion (typically 2 h). At
this time the solution was quenched by addition of satd NH4Cl
solution (2.0 mL) at 0 °C and warmed to rt, and H2O (15 mL)
was added. The solution was extracted with EtOAc (3 ꢀ 15 mL),
and the combined organic phases were washed with brine
(15 mL), dried (MgSO4), and concentrated. Chromatography
(50% EtOAc/hexanes) gave 0.045 g (84%) of colorless oil:
[R]20 þ200.00 (c 1.78, CHCl3); H NMR (CDCl3) δ 2.04 (s,
1
D
3H), 2.32 (m, 1H), 2.41 (s, 3H), 2.71 (m, 1H), 3.35 (m, 1H), 4.48
(m, 1H), 4.54 (bd, J = 10.8 Hz, 1H), 5.85 (m, 1H), 7.30 (bd, J =
7.6 Hz, 2H), 7.54 (bd, J = 8.0 Hz, 2H); 13C NMR (CDCl3) δ 21.3,
31.0, 33.4, 53.0, 60.0, 125.8, 129.5, 131.8, 132.8, 141.4, 208.5;
J. Org. Chem. Vol. 75, No. 11, 2010 3819

Davis and Theddu
JOCArticle
(MgSO4), and concentrated. Chromatography (50% EtOAc/
hexanes) afforded 0.016 g (89%) of a white solid, mp 81-82 °C:
[R]20D -6.15 (c 0.32, CHCl3); 1H NMR (CDCl3) δ 2.21 (s, 3H),
2.60 (m, 1H), 2.68 (m, 1H), 4.11 (m, 1H), 4.82 (m, 1H), 5.38 (d,
J = 10.4 Hz, 1H), 5.58 (m, 1H), 5.83 (m, 1H), 6.99 (m, 2H), 7.39
(m, 2H), 7.54 (m, 3H), 7.72 (m, 2H); 13C NMR (CDCl3) δ 21.4,
35.8, 45.6, 60.9, 126.9, 128.3, 128.4, 128.5, 129.5, 131.3, 131.7,
133.2, 136.0, 137.4, 143.0, 199.7; IR (film) 3265, 1673, 1596
cm-1. HRMS calcd for C19H20NO3S (M þ H) 342.1158, found
342.1152.
(1R,2S)-(þ)-2-(N-p-Toluenesulfonylamino)-cyclopent-3-enyl
Methyl Ketone (17). Chromatography (solvent) gave (91%) of a
solid, mp 131-132 °C: [R]20D þ69.54 (c 0.54, CHCl3); 1H NMR
(CDCl3) δ 2.13 (s, 3H), 2.36 (m, 1H), 2.43 (s, 3H), 2.69 (m, 1H),
3.41 (dt, J = 6.0 Hz, J = 8.8 Hz, 1H), 4.68 (m, 1H), 4.88 (d,
J = 10.4 Hz, 1H), 5.16 (m, 1H), 5.78 (m, 1H), 7.31 (bd, J = 8.0 Hz,
2H), 7.73 (td, J = 8.0 Hz, J = 2.0 Hz, 2H); 13C NMR (CDCl3) δ
21.5, 30.5, 33.0, 52.2, 60.1, 127.1, 129.3, 129.8, 133.3, 137.8,
143.6, 207.9; IR (film) 3220, 3055, 1709, 1601 cm-1. HRMS
calcd for C14H18NO3S (M þ H) 280.1007, found 280.1001.
Acknowledgment. We thank Dr. Charles DeBrosse, Direc-
tor of Temple’s NMR facilities, for aid in the NOE experime-
nts. This work was supported by a grant from National Insti-
tutes of General Medicinal Sciences (GM 57870).
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.
3820 J. Org. Chem. Vol. 75, No. 11, 2010