Asymmetric synthesis of α,α-dibranched propargylamines by acetylide additions to N-tert-butanesulfinyl ketimines

Article abstract of DOI:10.1021/jo061160h

Addition of lithium acetylides prepared from 1-pentyne, phenylacetylene, and trimethylsilylacetylene to diverse N-tert-butanesulfinyl ketimines affords a range of α,α-dibranched propargyl sulfinamides in generally good yields (up to 87%) and with high dia

Full text of DOI:10.1021/jo061160h

lithium acetylides to N-sulfinyl ketimines with uniformly high
diastereoselectivity.7
Asymmetric Synthesis of r,r-Dibranched
Propargylamines by Acetylide Additions to
N-tert-Butanesulfinyl Ketimines
We previously reported the asymmetric synthesis of tertiary
carbinamines by the dropwise addition of the Me3Al complex
of N-tert-butanesulfinyl ketimines to solutions of alkyl-, vinyl-,
and aryllithiums in hydrocarbon solvents.7,8 Accordingly, N-tert-
butanesulfinyl ketimines (1) were first prepared in good yields
according to the previously described method (Scheme 1).9 The
1,2-addition of lithium acetylides to N-sulfinyl ketimines (1)
was performed by dropwise addition of a -78 °C solution of 1
and Me3Al in toluene to a solution of in situ generated lithium
acetylide precooled to -78 °C (Scheme 2). Uniformly high
diastereoselectivities were observed for a broad range of
ketimine and acetylide inputs, and additions to a majority of
the N-sulfinyl ketimines proceeded in good yields (Table 1).
For those substrate combinations where a minor diastereomer
was obtained, purification by chromatography readily provided
the diastereomerically pure major isomer. The stereochemical
assignment for the major diastereomer of the addition reactions
is based on an X-ray crystal structure of inhibitor 3 (Figure 1)
that was cocrystallized with the cysteine protease cathepsin S
at 1.5 Å resolution.10 This assignment is consistent with the
sense of induction observed for the addition of alkyl- and
Andrew W. Patterson and Jonathan A. Ellman*
Department of Chemistry, UniVersity of California,
Berkeley, California 94720
jellman@uclink.berkeley.edu
ReceiVed June 6, 2006
Addition of lithium acetylides prepared from 1-pentyne,
phenylacetylene, and trimethylsilylacetylene to diverse N-
tert-butanesulfinyl ketimines affords a range of R,R-di-
branched propargyl sulfinamides in generally good yields
(up to 87%) and with high diastereoselectivities (up to >99:
1). Acidic cleavage of the tert-butanesulfinyl group provides
the free R,R-dibranched propargylamines.
(2) For leading references, see: (a) Taverse, J. F.; Hoveyda, A. H.;
Snapper, M. L. Org. Lett. 2003, 5, 3273-3275. (b) Aschwanden, P.;
Stephenson, C. R. J.; Carreira, E. M. Org. Lett. 2006, 8, 2437-2440. (c)
Bisai, A.; Singh, V. K. Org. Lett. 2006, 8, 2405-2408. (d) Lo, V. K.-Y.;
Liu, Y.; Wong, M.-K.; Che, C.-M. Org. Lett. 2006, 8, 1529-1532. (e) Wu,
T. R.; Chong, J. M. Org. Lett. 2006, 8, 15-18. (f) Gommermann, N.;
Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42,
5763-5766. (g) Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int.
Ed. 2002, 41, 2535-2538. (h) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2002,
124, 5638-5639. (X) Jiang, B.; Si, Y.-G. Tetrahedron Lett. 2003, 44, 6767-
6768. (i) Si, Y.-G.; Huang, H.; Jiang, B. Chin. J. Org. Chem. 2004, 24,
1389-1395. (j) Benaglia, M.; Negri, D.; Dell’Anna, G. Tetrahedron Lett.
2004, 45, 8705-8708. (k) Ji, J.-X.; Wu, J.; Chan, A. S. Proc. Natl. Acad.
Sci. 2005, 102, 11196-11200. (l) Enders, D.; Schankat, J. HelV. Chim.
Acta 1995, 78, 970-992. For a review, see: (m) Blanchet, J.; Bonin, M.;
Micouin, L. Org. Prep. Proced. Int. 2002, 34, 459.
(3) Hou and co-workers have recently reported using N-tert-butanesulfinyl
aldimines in the synthesis of R-branched propargylamines: (a) Ding, C.-
H.; Chen, D.-D.; Luo, Z.-B.; Dai, L.-X.; Hou, X.-L. Synlett 2006, 1272-
1274. Other examples include: (b) Tang, T. P.; Volkman, S. K.; Ellman,
J. A. J. Org. Chem. 2001, 66, 8772-8778. (c) Barrow, J. C.; Ngo, P. L.;
Pellicore, J. N.; Selnick, H. G.; Nantermet, P. G. Tetrahedron Lett. 2001,
42, 2051-2054. (d) Kuduk, S. D.; DiPardo, R. M.; Chang, R. K.; Ng, C.;
Bock, M. G. Tetrahedron Lett. 2004, 45, 6641-6643. (e) Lettan, R. B., II.;
Scheidt, K. A. Org. Lett. 2005, 7, 3227-3230.
(4) (a) Crucianelli, M.; De Angelis, F.; Lazzaro, F.; Malpezzi, L.;
Volonterio, A.; Zanda, M. J. Fluorine Chem. 2004, 125, 573-577. (b) Jiang,
B.; Si, Y.-G. Angew. Chem., Int. Ed. 2004, 43, 216-218. (c) Kauffman, G.
S.; Harris, G. D.; Dorow, R. L.; Stone, B. R. P.; Parsons, R. L., Jr.; Pesti,
J. A.; Magnus, N. A.; Fortunak, J. M.; Confalone, P. N.; Nugent, W. A.
Org. Lett. 2000, 2, 3119-3121. (d) Huffman, M. A.; Yasuda, N.; DeCamp,
E. A.; Grabowski, E. J. J. J. Org. Chem. 1995, 60, 1590-1594. (e) Harwood,
L. M.; Vines, K. J.; Drew, M. G. B. Synlett 1996, 1051-1053.
(5) Wood, W. J. L.; Patterson, A. W.; Tsuruoka, H.; Jain, R. K.; Ellman,
J. A. J. Am. Chem. Soc. 2005, 127, 15521-15527.
(6) Shaw at Merck Research Laboratories previously reported moderate
selectivity and good yields in the addition of pentynylmagnesium bromide
to an R-aryl-R-heteroaryl-N-tert-butanesulfinyl ketimine to generate an R,R-
dibranched propargylamine. Shaw, A. W.; de Solms, J. S. Tetrahedron Lett.
2001, 42, 7173-7176.
Propargylamines are important intermediates in the synthesis
of many drugs, drug leads, and natural products,1 and therefore,
considerable effort has been dedicated to the development of
efficient asymmetric methods for their construction. Although
a number of efficient approaches for the synthesis of enantio-
merically enriched R-branched propargylamines have been
reported,2,3 very few methods are applicable to the asymmetric
synthesis of R,R-dibranched propargylamines and these are
limited to a narrow set of structural types.4-6 In the context of
the synthesis of potent, nonpeptidic cathepsin S inhibitors, we
required efficient entry to enantiomerically pure R,R-dibranched
propargylamines.5 Here, we report a general method for the
asymmetric synthesis of these compounds by the addition of
(1) For selected examples, see: (a) Brik, A.; Alexandratos, J.; Lin, Y.-
C.; Elder, J. H.; Olson, A. J.; Wlodawer, A.; Goodsell, D. S.; Wong, C.-H.
ChemBioChem 2005, 6, 1167-1169. (b) Corbett, J. W.; Ko, S. S.; Rodgers,
J. D.; Gearhart, L. A.; Magnus, N. A.; Bacheler, L. T.; Diamond, S.; Jeffrey,
S.; Klabe, R. M.; Cordova, B. C.; Garber, S.; Logue, K.; Trainor, G. L.;
Anderson, P. S.; Erickson-Viitanen, S. K. J. Med. Chem. 2000, 43, 2019-
2030. (c) Britcher, S. F.; Goldman, M. E.; Huff, J. R.; Lumma, W. C.;
Lyle, T. A.; Payne, L. S.; Quesada, M. L.; Sanders, W. M.; Sanderson, P.
E.; Tucker, T. J.; Young, S. D. Eur. Pat. Appl. EP-A-0 530994, 1992. (d)
Trost, B. M.; Chung, C. K.; Pinkerton, A. B. Angew. Chem., Int. Ed. 2004,
43, 4327-4329. (e) Davidson, M. H.; McDonald, F. E. Org. Lett. 2004, 6,
1601-1603. (f) Brennan, C. J.; Pattenden, G.; Rescourio, G. Tetrahedron
Lett. 2003, 44, 8757-8760. (g) Porco, J. A., Jr.; Schoenen, F. J.; Stout, T.
J.; Clardy, J.; Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 7410. For a
review, see: (h) Aschwanden, P.; Carreira, E. M. Acetylene Chemistry:
Chemistry, Biology, and Material Science; Diederich, F., Stang, P. J.,
Tykwinski, R. R., Eds.; Wiley: Weinheim, 2005.
(7) For a review on applications of tert-butanesulfinamide, see: Ellman,
J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984-995.
(8) Cogan, D. A.; Liu, G.; Ellman, J. A. Tetrahedron 1999, 55, 8883-
8904.
(9) Liu, G.; Cogan, D. A.; Owens, T.; Tang, T. P.; Ellman, J. A. J. Org.
Chem. 1999, 64, 1278-1284.
10.1021/jo061160h CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/04/2006
7110
J. Org. Chem. 2006, 71, 7110-7112

TABLE 1. 1,2-Additions of Alkynyllithiums to N-Sulfinyl Ketimines 1
N-sulfinyl ketimine 1
alkynyllithium addition
propargyl sulfinamide 2
entry
compound
R1
R2
R3
conditions
compound
dr
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1a
1a
1b
1c
1d
1e
1f
methyl
methyl
methyl
methyl
methyl
methyl
methyl
ethyl
iso-propyl
iso-propyl
iso-propyl
tert-butyl
cyclohexyl
trans-4-methylcyclohexyl
cis-4-methylcyclohexyl
cyclohexyl
cyclohexyl
n-butyl
phenyl
phenyl
n-propyl
phenyl
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
toluene w/Me3Al
toluene w/Me3Al
toluene w/Me3Al
toluene w/Me3Al
toluene w/Me3Al
toluene w/Me3Al
toluene w/Me3Al
toluene w/Me3Al
toluene
2a
2b
2c
2d
2e
2f
2g
2h
2h
2i
>99:1a
95:5a
71b
74b
87b
81b
73b
80b
85b
80b
60b
46b
20e
11e
<5e
>99:1a
>99:1a
>99:1a
>99:1a
97:3a
90:10c
89:11c
95:5a
1f
ethyl
1gd
1h
1h
1h
methyl
methyl
methyl
methyl
toluene w/Me3Al
toluene w/Me3Al
toluene
2j
2j
2j
86:14c
89:11c
ND
phenyl
THF
a Diastereomeric ratio was determined by HPLC assay. b Isolated yield of diastereomerically and analytically pure material after chromatography.
c Diastereomeric ratio was determined by NMR analysis. d N-Sulfinyl ketimine 1g exists as a 5:1 mixture of E and Z isomers. e Yield determined by NMR
analysis using hexamethylbenzene as an external standard.
SCHEME 1
SCHEME 3
This minor byproduct presumably formed by competitive and
reversible R-deprotonation of the N-sulfinyl ketimine to give
the thermodynamically favored trans-4-methylcyclohexylsulfi-
nyl ketimine epimer followed by acetylide addition.
SCHEME 2
Additionally, the more sterically hindered N-sulfinyl ketimine
1f reacted in good yield with only a modest drop in diastereo-
selectivity to give propargyl sulfinamide 2h. In this example,
we also see the effect of the Me3Al Lewis acid on conversion
to product. Although only a modest drop in the diastereoselec-
tivity was observed without the Me3Al additive, a significant
drop in the yield occurred (entry 8 vs entry 9).
An anomalously low yield was seen for the non-R-branched
N-sulfinyl ketimine 1g and the aryl-substituted N-sulfinyl
ketimine 1h, with competitive deprotonation to form the
metalloenamine likely hampering the reaction progress as
evidenced by the large amount of recovered starting N-sulfinyl
ketimine upon reaction workup. Neither removal of Me3Al
(entry 12) nor use of THF as solvent (entry 13) improved the
yield of the product.
Reaction of the trimethylsilyl-functionalized propargyl sul-
finamide products with tetrabutylammonium fluoride (TBAF)
readily provides the synthetically useful terminal acetylenes as
demonstrated for the conversion of sulfinamide 2c to the
terminal acetylene 4 in near quantitative yield (Scheme 3). The
N-tert-butanesulfinyl group also may be cleaved under acidic
methanolysis conditions to give the free amine hydrochloride
salt in near quantitative yield, as illustrated for the conversion
of 4 to the propargylamine hydrochloride salt 5 (Scheme 3).
In conclusion, additions of acetylide nucleophiles to N-tert-
butanesulfinyl ketimines provide a general and efficient method
for the asymmetric synthesis of R,R-dibranched propargyl-
amines, with good yields and high diastereoselectivities observed
for a range of acetylides and N-sulfinyl ketimine starting
materials.
aryllithium reagents to N-sulfinyl ketimines.8 Inhibitor 3 was
prepared by the reaction of a derivative of propargylamine 2c
and an R-azido acid via a copper-catalyzed 1,3-dipolar cycload-
dition.
n-Propylethynyllithium and phenylethynyllithium were added
to N-sulfinyl ketimine 1a generating the respective propargyl
sulfinamide products 2a and 2b, in good yield and with high
diastereoselectivity (Table 1). (Trimethylsilyl)ethynyllithium was
also added to a number of N-sulfinyl ketimines with good yields
and diastereoselectivities seen for a range of substrates. The
R-branched isopropyl (1a), tert-butyl (1b), cyclohexyl (1c), and
trans-4-methylcyclohexyl (1d) N-sulfinyl ketimines provided
the desired products in high yields and without any detectable
minor diastereomer (entries 4-7). The R-branched cis-4-methyl-
cyclohexyl N-sulfinyl ketimine 1e also reacted in good yield
and with high diastereoselectivity to give propargyl sulfinamide
2g. Interestingly, the minor diastereomer proved to be propargyl
sulfinamide 2f on the basis of NMR and HPLC comparisons.
FIGURE 1. Cathepsin S inhibitor derived from propargyl sulfinamide
2c.
(10) PDB ID: 2H7J. Also see: Patterson, A. W.; Wood, W. J. L.; Ellman,
J. A. J. Med. Chem., submitted.
J. Org. Chem, Vol. 71, No. 18, 2006 7111

(Ss, S)-(+)-N-(1-Isopropyl-1-methyl-prop-2-ynyl)-2-methyl-
propanesulfinamide (4). To a 0.1 M solution of propargyl
sulfinamide 2c (5.10 g, 17.7 mmol) in 180 mL of THF cooled in
an ice-water bath was added 16.8 g of TBAF (53.2 mmol). The
solution was stirred for 2 h at room temperature, and then the
solution was poured into saturated aqueous NH4Cl with rapid
stirring. The resulting suspension was transferred to a separatory
funnel and extracted three times with Et2O. The combined organic
portions were dried (Na2SO4), filtered, and concentrated. Silica gel
chromatography (hexane/ethyl acetate ) 1:1) provided propargyl
Experimental Section
General Procedure for the 1,2-Addition of Alkynyllithiums
to N-tert-Butanesulfinyl Ketimines with Me3Al. To a 0.85 M
solution of alkyne (3.0-3.5 equiv) in toluene at -78 °C was added
butyllithium (2.2 equiv) as a solution in hexanes. The resulting
solution was stirred for ca. 15 min before a stirred -78 °C toluene
solution of N-sulfinyl ketimine 1 (1.0 equiv, 0.35 M) and Me3Al
(1.2 equiv) was slowly added via cannula. Stirring was continued
at -78 °C for 2 h, and then the solution was allowed to warm to
room temperature over 4 h. Stirring was continued at room
temperature for 10-30 h before the mixture was cooled in an ice-
water bath. Saturated aqueous Na2SO4 was added dropwise until
gas was no longer evolved upon addition. The slurry was filtered,
and the filter cake was rinsed with EtOAc. The filtrate was dried
(Na2SO4), filtered, and concentrated. The diastereomeric ratio was
determined by HPLC or by NMR with hexamethylbenzene as an
external standard. If the starting N-sulfinyl ketimine was not fully
reacted, the crude material was dissolved in CH3OH and a 1 M
aqueous solution of CH3CO2H (2:1 ratio) was added. The solution
was stirred at room temperature for 8-12 h to hydrolyze the
N-sulfinyl ketimine. The resulting slurry was then concentrated to
remove the CH3OH, and brine was added. The slurry was then
extracted three times with ethyl acetate, dried with Na2SO4, filtered,
and concentrated. Chromatography afforded the diastereomerically
pure propargyl sulfinamides 2.
sulfinamide 4 (3.77 g, 99%) as a white solid: mp 98-100 °C; [R]20
D
) +72.1 (c 1.0, CHCl3); IR 1015, 1031, 1382, 2104, 2953, 3210,
3262 cm-1; 1H NMR (400 MHz) δ 0.92 (d, J ) 6.8, 3H), 0.95 (d,
J ) 6.8, 3H), 1.10 (s, 9H), 1.37 (s, 3H), 1.82 (septet, J ) 6.8, 1H),
2.37 (s, 1H), 3.18 (s, 1H); 13C NMR (100 MHz) δ 16.9, 17.4, 22.3,
25.0, 38.1, 55.8, 56.6, 72.8, 85.8. Anal. Calcd for C11H21NOS: C,
61.35; H, 9.83; N, 6.50. Found: C, 61.52; H, 10.13; N, 6.64.
(S)-(+)-1-Isopropyl-1-methyl-prop-2-ynylamine Hydrochlo-
ride (5). To a 0.15 M solution of propargyl sulfinamide 4 (3.77 g,
17.5 mmol) in 120 mL of CH3OH was added 13.0 mL of 4 M HCl
in 1,4-dioxane (52.5 mmol). The solution was stirred for 1.5 h and
concentrated to yield propargylamine 5 (2.55 g, 99%) as a white
solid: dec 245 °C; [R]20 ) +2.1 (c 1.0, CH3OH); IR 556, 708,
D
1385, 1513, 1608, 2117, 2873 (br), 3221 cm-1; H NMR (CD3-
1
OD, 400 MHz) δ 0.93 (d, J ) 6.8, 3H), 0.97 (d, J ) 6.8, 3H), 1.60
(s, 3H), 2.10 (septet, J ) 6.8, 1H), 3.30 (s, 1H); 13C NMR (CD3-
OD, 100 MHz) δ 17.8, 17.9, 24.5, 37.7, 56.9, 78.1, 81.5. Anal.
Calcd for C7H14NCl: C, 56.94; H, 9.56; N, 9.49. Found: C, 57.01;
H, 9.79; N, 9.27.
(Ss,S)-(+)-N-(1-Isopropyl-1-methyl-3-trimethylsilanyl-prop-
2-ynyl)-2-methylpropanesulfinamide (2c). The general procedure
was followed with a mixture of 13.0 mL of (trimethylsilyl)ethyne
(93.6 mmol), 36.0 mL of butyllithium (68.6 mmol, 1.9 M in
hexanes), 5.90 g of N-sulfinyl ketimine 1a (31.2 mmol), and 3.55
mL of Me3Al (37.0 mmol) in 193 mL total volume of toluene. The
diastereomeric ratio was determined to be >99:1 by HPLC assay.
Hydrolysis followed by purification by silica gel chromatography
(hexane/ethyl acetate ) 2:1) provided diastereomerically pure
propargyl sulfinamide 2c (7.81 g, 87%) as a white solid: mp 64-
Acknowledgment. This work was supported by the National
Science Foundation (CHE-0446173) and the National Institutes
of Health (GM54051).
66 °C; [R]20 ) +54.0 (c 1.0, CHCl3); IR 758, 839, 1010, 1025,
D
Supporting Information Available: General experimental
methods; synthesis and compound characterization for N-sulfinyl
ketimines 1; and specific reaction conditions and complete com-
pound characterization of propargyl sulfinamides 2. This material
is available free of charge via the Internet at http://pubs.acs.org.
1248, 2174, 2957, 3103 cm-1; 1H NMR (400 MHz) δ 0.15 (s, 9H),
1.00 (d, J ) 6.8, 3H), 1.03 (d, J ) 6.8, 3H), 1.20 (s, 9H), 1.43 (s,
3H), 1.93 (septet, J ) 6.8, 1H), 3.22 (s, 1H); 13C NMR (100 MHz)
δ -0.2, 17.1, 17.8, 22.5, 25.3, 38.2, 56.1, 57.7, 88.9, 108.0. Anal.
Calcd for C14H29NOSSi: C, 58.48; H, 10.17; N, 4.87. Found: C,
58.77; H, 10.37; N, 5.13.
JO061160H
7112 J. Org. Chem., Vol. 71, No. 18, 2006