Asymmetric α-alkylation of N′-tert-butanesulfinyl amidines. Application to the total synthesis of (6 R,7 S)-7-amino-7,8-dihydro-α- bisabolene

Full text of DOI:10.1021/ja044753n

Published on Web 11/12/2004
Asymmetric r-Alkylation of N′-tert-Butanesulfinyl Amidines. Application to the
Total Synthesis of (6R,7S)-7-Amino-7,8-dihydro-r-bisabolene
Takuya Kochi and Jonathan A. Ellman*
Center for New Directions in Organic Synthesis, Department of Chemistry, UniVersity of California,
Berkeley, California 94720
Received August 31, 2004; E-mail: jellman@berkeley.edu
The addition of nucleophiles to imines1 and metalloenamine
Table 1. Synthesis of N′-tert-Butanesulfinyl Amidines 4
additions to electrophiles2 are two of the most important methods
for the preparation of diverse amine structures. The addition of a
variety of nucleophiles to N-sulfinyl imines is increasingly being
used for the asymmetric synthesis of a broad range of amine-
containing compounds,3,4 and recently, the highly diastereoselective
addition of metalloenamines derived from N-sulfinyl ketimines to
aldehydes has been developed for the asymmetric synthesis of 1,3-
amino alcohols.5 However, in the course of studies on the
applicability of the N-sulfinyl metalloenamine additions to other
electrophiles, R-alkylations of the metalloenamines with alkyl
halides were not successful. We attributed these results to the strong
electron-withdrawing character of the sulfinyl group, which attenu-
ates the nucleophilicity of the metalloenamine. Therefore, we
envisioned that the significantly more basic metalloenamines
derived from N′-sulfinyl amidines would be sufficiently reactive
to enable R-alkylation. Herein we describe the highly diastereo-
selective R-alkylation of N′-tert-butanesulfinyl amidines and the
versatility of the resulting R-alkylation products in the asymmetric
synthesis of amines that contain both R- and â-stereocenters. The
utility of this chemistry is further demonstrated by the first
asymmetric synthesis of the antimicrobial marine natural product
(6R,7S)-7-amino-7,8-dihydro-R-bisabolene.6
entry
R
R
′
yield of 3 (%)a
product 4
yield of 4 (%)a
1b
2c
3c
Me
Ph
Bn
Et
Me
Me
94
97
97
4a
4b
4c
88
83
88
a Isolated yield. b First step was carried out with 1 equiv of 1 and 3 equiv
of 2 for 3 h. c First step was carried out with 1 equiv of 1 and 1.5 equiv of
2 for 12 h.
Table 2. Asymmetric R-Alkylation of N′-Sulfinyl Amidines 4
Synthesis of N′-tert-butanesulfinyl amidines 4 can be achieved
in two steps from ortho esters (Table 1).7 Condensation of tert-
butanesulfinamide 1 and ortho esters 2 with 0.5 mol % p-TsOH,
followed by the reaction of the imidate products 3 with morpholine
using NaCN as a catalyst, afforded 4 in high yields.
Examination of the R-alkylation of N′-tert-butanesulfinyl amidines
with a number of bases and solvents established that deprotonation
of 4 with KHMDS in THF/toluene, followed by reaction with alkyl
halides, provided the alkylated amidine products 5 in high yields
and with excellent diastereoselectivities (Table 2). The alkylation
of amidine 4a was performed at -78 °C with several allyl bromides
and benzyl bromide to afford 5a-d in high yields with >98:2
diastereoselectivities. Reactions with the more hindered amidines
4b and 4c required an increase in the reaction temperature to -40
°C, but the alkylation products were still obtained with >96:4
diastereoselectivities (entries 5-7).
Successful transformation of the amidine R-alkylation products
to N-sulfinyl aldimines and ketimines was essential to achieving a
powerful and versatile method for the asymmetric synthesis of
amines. Among a number of reducing agents examined to convert
the amidines to aldimines, Red-Al was found to be the most
effective, with reaction of 5d with Red-Al at -40 °C providing
the desired aldimine 6d in 86% yield (Scheme 1).8 Addition of a
mixture of an organolithium reagent and CeCl3 proved to be most
effective for converting the amidines to ketimines,9 with the reaction
of 5d with MeLi and CeCl3 at -48 °C affording methyl ketimine
7d in 87% yield. It is noteworthy that no epimerization occurred
a Diastereomeric ratio. b Isolated yield. c Performed with 3 equiv of MeI.
in either the Red-Al reduction or the methyl cerium addition
reactions. As previously reported, N-tert-butanesulfinyl imines are
versatile precursors for the asymmetric synthesis of protected chiral
amines.3 For example, the addition of MeMgBr to 6d provided anti-
8d in 95% yield with 99:1 dr.10 Moreover, reduction of ketimine
7d could be accomplished with high selectivity to obtain either
amine stereoisomer, with L-Selectride affording anti-8d in 89%
yield with 96:4 dr and with NaBH4 in the presence of Ti(OEt)4
affording syn-8d in 86% yield with 96:4 dr.11 The structure of anti-
8d has been determined by X-ray crystallography and thus
establishes both the sense of induction in the alkylation step (Table
9
15652
J. AM. CHEM. SOC. 2004, 126, 15652-15653
10.1021/ja044753n CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
reagent addition to N-sulfinyl ketimines provides the only general
method for the asymmetric synthesis of tertiary carbinamines.12
Gratifyingly, precomplexation of imine 16 with Me3Al in toluene
at -78 °C, followed by addition of the organolithium reagent in
hexanes, provided 17 as a single diastereomer in 56% yield. Both
the Me3Al activating agent and the use of noncoordinating sol-
vents were essential for suppressing competitive R-deprotonation.
Cleavage of the N-sulfinyl group from 17 under acidic conditions
then provided (6R,7S)-7-amino-7,8-dihydro-R-bisabolene 18 in 87%
yield.
In summary, the highly diastereoselective R-alkylation of N′-
tert-butanesulfinyl amidines has been developed along with methods
for converting the alkylation products to enantiomerically enriched
amines that incorporate both R- and â-stereocenters. As evidenced
by the first asymmetric synthesis of (6R,7S)-7-amino-7,8-dihydro-
R-bisabolene, this method should provide for the efficient asym-
metric syntheses of a wide variety of amine-containing compounds.
Scheme 2
Acknowledgment. We gratefully acknowledge the NSF for
financial support. The Center for New Directions in Organic
Synthesis is supported by Bristol-Myers Squibb as a Sponsoring
Member and Novartis as a Supporting Member. We thank Dr. Fred
Hollander and Dr. Allen Oliver of the UC Berkeley CHEXRAY
facility for carrying out the X-ray diffraction studies.
Supporting Information Available: Synthetic procedures, char-
acterization, and stereochemical determination of new compounds (CIF,
PDF). This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) (a) Bloch, R. Chem. ReV. 1998, 98, 1407-1438. (b) Enders, D.;
Reinhold: U. Tetrahedron: Asymmetry 1997, 8, 1895-1946.
(2) (a) Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D. Tetrahedron
2002, 58, 2253-2329. (b) Bergbreiter, D. E.; Newcomb, M. In Alkylation
of Imine and Enamine Salts. In Asymmetric Synthesis; Morrison, J. D.,
Ed,; Academic Press: Orlando, FL, 1984; Vol. 2, pp 243-273. (c)
Lutomski, K. A.; Meyers, A. I. Asymmetric Synthesis via Chiral
Oxazolines. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic
Press: Orlando, FL, 1984; Vol. 3, pp 213-274.
(3) For additions to tert-butanesulfinyl imines, see: (a) Ellman, J. A.; Owens,
T. D.; Tang. T. P. Acc. Chem. Res. 2002, 35, 984-995. (b) Kochi, T.;
Mukade, T.; Ellman, J. A. J. Synth. Org. Chem., Jpn. 2004, 62, 128-
139. (c) Higashibayashi, S.; Kohno, M.; Goto, T.; Suzuki, K.; Mori, T.;
Hashimoto, K.; Nakata, M. Tetrahedron Lett. 2004, 45, 3707. (d) DeSolms,
S. J.; Ciccarone, T. M.; MacTough, S. C. et al. J. Med. Chem. 2003, 46,
2973. (e) Jung, P. M.; Beaudegnies, E.; DeMesmaeker, A.; Wendeborn,
S. Tetrahedron Lett. 2003, 44, 293-297. (f) Kuduk, S. D.; DiPardo, R.
M.; Chang, R. K.; Ng, C.; Bock, M. G. Tetrahedron Lett. 2004, 45, 6641-
6643. (g) Pflum, D. A.; Krishnamurthy, D.; Han, Z.; Wald, S. A.;
Senanayake, C. H. Tetrahedron Lett. 2002, 43, 923-926.
2) and the relative stereochemistry obtained in the imine addition
steps (Scheme 1).
To demonstrate the utility of this methodology, the first asym-
metric total synthesis of (6R,7S)-7-amino-7,8-dihydro-R-bisabolene6
18 was carried out (Scheme 2). The amidine substrate 13 for
R-alkylation was synthesized in four steps from commercially
available ortho ester 9. Condensation of 1 with 9 afforded imidate
10 in 76% yield. Because the coupling of 10 with isopropenyl-
magnesium bromide did not provide 12, bromide 10 was converted
to iodide 11, which was successfully coupled with the Grignard
reagent and CuI. Imidate 12 was converted to 13 in 93% yield under
the standard reaction conditions for the conversion of the imidates
to the amidines. Allylation of 13 was then performed at -78 °C to
afford a single diastereomer of 14 in 82% yield, and amidine 14
was subsequently converted to ketimine 15 with MeLi and CeCl3
in 82% yield. Ring-closing metathesis with the Grubbs second-
generation catalyst then gave 16 in high yield.
(4) For additions to arenesulfinyl imines, see: Zhou, P.; Chen, B.-C.; Davis,
F. A. Tetrahedon 2004, 60, 8003-8030.
(5) (a) Kochi, T.; Tang, T. P.; Ellman J. A. J. Am. Chem. Soc. 2003, 125,
11276-11282. (b) Kochi, T.; Tang, T. P.; Ellman J. A. J. Am. Chem.
Soc. 2002, 124, 6518-6519.
(6) (a) Sullivan, B. W.; Faulkner, D. J.; Okamoto, K. T.; Chen, M. H. M.;
Clardy, J. J. Org. Chem. 1986, 51, 5134-5136. (b) Ichikawa, Y. Chem.
Lett. 1990, 1347-1350.
(7) For syntheses of some N-sulfinyl imidates and N′-sulfinyl amidines:
Owens, T. D.; Souers, A. J.; Ellman, J. A. J. Org. Chem. 2003, 68, 3-10.
(8) Reduction of esters to aldehydes with modified Red-Al: Abe, T.; Haga,
T.; Negi, S.; Morita, Y.; Takayanagi, K.; Hamamura, K. Tetrahedron 2001,
57, 2701-2710.
(9) Synthesis of ketones from morpholine amides by organocerium addition:
(a) Badioli, M.; Ballini, R.; Bartolacci, M.; Bosica, G.; Torregiani, E.;
Marcantoni, E. J. Org. Chem. 2002, 67, 8938-8942. (b) Kurosu, M.; Kishi,
Y. Tetrahedron Lett. 1998, 39, 4793-4796.
(10) Cogan, D. A.; Liu, G.; Ellman, J. A. Tetrahedron 1999, 55, 8883-8904.
(11) Borg, G.; Cogan, D. A.; Ellman, J. A. Tetrahedron Lett. 1999, 40, 6709-
6712.
(12) Steinig, A. G.; Spero, D. M. Org. Prep. Proced. Int. 2000, 32, 205-234.
One of the key steps in the synthesis was organolithium addition
to 16 to provide the tertiary carbinamine 17. Notably, organometallic
JA044753N
9
J. AM. CHEM. SOC. VOL. 126, NO. 48, 2004 15653