Design, synthesis, and utility of a support-bound tert-butanesulfinamide [15]

Full text of DOI:10.1021/ja016349j

J. Am. Chem. Soc. 2001, 123, 10127-10128
10127
Beginning with tertiary alcohol 2, chlorination in concentrated
HCl was immediately followed by Grignard formation at 72 °C
(Scheme 1). Sulfinyl chloride 4 is then prepared in a one-pot
sequence by addition of Grignard 3 to sulfur dioxide condensed
at -48 °C followed by chlorination with thionyl chloride.
Design, Synthesis, and Utility of a Support-Bound
tert-Butanesulfinamide
Dean R. Dragoli, Matthew T. Burdett, and
Jonathan A. Ellman*
Scheme 1a
Center for New Directions in
Organic Synthesis, Department of Chemistry
UniVersity of California, Berkeley, California 94720
ReceiVed June 6, 2001
Amines are one of the most prevalent functionalities found in
drugs. Not surprisingly, the synthesis of amine-containing com-
pounds is a major focus of solid-phase synthesis, and a number
of extensively utilized linkers have been developed for this
purpose.1 However, linkers for the asymmetric synthesis of amines
have received only limited development despite their potential
importance for the multistep asymmetric synthesis of drug leads
and natural product-like compounds.2 Herein, we report a novel
and efficient synthesis of a support-bound tert-butanesulfinamide
derivative 1 (SBS linker) and demonstrate the utility of this linker
not only for the asymmetric synthesis of enantioenriched amines
but also for the multistep asymmetric synthesis of pavine and
isopavine alkaloids.
a
Reagents and conditions: (a) conc HCl; (b) Mg, THF, 72 °C; (c)
SO2, THF, -48 °C then SOCl2; (d) cat. DMAP, i-Pr2EtN, THF, -78 °C,
(S)-2-amino-1,1,2-triphenylethanol; (e) Li, NH3, NH4Cl, THF, -48 °C;
(f) bromopolystyrene, 5% Pd(PPh3)4, 2 M Na2CO3, 72 °C.
By taking advantage of the configurational lability of sulfinyl
chlorides, we next developed a dynamic resolution process for
the high-yield conversion of racemic 4 to enantiopure sulfinamide
6. In particular, we extensively explored the addition of chiral
alcohol and amine nucleophiles to provide a crystalline, diaste-
reomerically pure sulfinyl intermediate that in a single step could
be converted to 6. Under optimal conditions (S)-2-amino-1,1,2-
triphenylethanol12 is added to sulfinyl chloride 4 with DMAP as
a sulfinyl transfer catalyst to proVide a 16:1 diastereomeric ratio
of sulfinamide products from which a single diastereomer 5 is
isolated in 76% yield after recrystallization. Without the DMAP
additive only a 2:1 diastereomer ratio is observed. This result
marks a dramatic advance in the dynamic resolution of sulfinyl
halides with chiral amine nucleophiles.13 In addition, the essential
role of catalytic DMAP suggests that chiral sulfinyl transfer
reagents might be developed for the catalytic asymmetric synthesis
of sulfinyl compounds.
Diastereomerically pure 5 is readily converted to enantiomeri-
cally pure sulfinamide 6 in 65% yield by dissolving metal reduc-
tion. Hydroboration of 6 and Suzuki coupling with bromopoly-
styrene provides the SBS linker 1.14
To correlate the solid- and solution-phase synthesis methods,
the synthesis of chiral R-branched amines was first explored
(Scheme 2). Condensation of aldehydes with 1 was efficiently
accomplished with Ti(OEt)4 as a Lewis acid and water scaven-
ger.15 Subsequent addition of ethylmagnesium bromide provided
the desired R-branched amine products 7. Cleavage from support
to obtain amine hydrochlorides 8 was then achieved using HCl
in a CH2Cl2/nBuOH solvent comixture for maximum swelling
The versatility of tert-butanesulfinamide for the asymmetric
synthesis of amines is well documented.3 First, in contrast to most
aldimines and ketimines, tert-butanesulfinyl imines are stable,
isolable synthetic intermediates.4 Second, addition of nucleophiles
provides with high stereoselectivity R-branched and R,R-di-
branched amines,5 R-6 and â-amino acids,7 R-trifluorometh-
ylamines,8 and 1,2-amino alcohols.9 Finally, the tert-butanesulfinyl
group7a and the corresponding oxidation product, the tert-butane-
sulfonyl group,10 serve as efficient acid-labile amine-protecting
groups. To take advantage of all aspects of tert-butanesulfinamide
chemistry we chose to link tert-butanesulfinamide to solid support
using an all-carbon tether. This unreactive tether ensures that the
support-bound derivative is compatible with a complete range of
organometallic addition and acidic cleavage reaction conditions.
We selected enantiomerically pure 6 as the key sulfinamide
intermediate since we have previously demonstrated that alkene-
appended functionality can be efficiently coupled to inexpensive
bromopolystyrene by hydroboration followed by Suzuki cross-
coupling.11
(1) For a recent review of solid-phase linkers: James, I. W. Tetrahedron
1999, 55, 4855-4946.
(2) Recently a linker was developed for the synthesis of R-branched primary
amines: Enders, D.; Kirchhoff, J. H.; Ko¨bberling, J.; Peiffer, T. H. Org. Lett.
2001, 3, 1241-1244.
(3) tert-Butanesulfinamide is also an effective chiral auxiliary for diaste-
reoselective enolate alkylation: Backes, B. J.; Dragoli, D. R.; Ellman, J. A.
J. Org. Chem. 1999, 64, 5472-5478.
(4) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J.
Org. Chem. 1999, 64, 1278-1284.
(5) (a) Cogan, D. A.; Liu, G.; Ellman, J. A. Tetrahedron 1999, 55, 8883-
8904. (b) Borg, G.; Cogan, D. A.; Ellman, J. A. Tetrahedron Lett. 1999, 40,
6709-6712.
(6) (a) Davis, F. A.; McCoull, W. J. Org. Chem. 1999, 64, 3396-3397.
(b) Davis, F. A.; Lee, S.; Zhang, H.; Fanelli, D. L.; J. Org. Chem. 2000, 65,
8704-8708. (c) Borg, G.; Chino, M.; Ellman, J. A. Tetrahedron Lett. 2001,
42, 1433-1436.
(12) Both enantiomers of the chiral amine are accessible: Bach, J.;
Berenguer, R.; Garcia, J.; Loscertales, T.; Vilarrasa, J. J. Org. Chem. 1996,
61, 9021-9025.
(13) A 3:1 ratio of sulfinamide diastereomers was obtained with (S)-
deoxyephedrine: Jacobus, J.; Mislow, K. J. Chem. Soc., Chem. Commun. 1968,
253-254. Chiral auxiliaries have been used to obtain aryl sulfinamide
diastereomers: Evans, D. A.; Faul, M. M.; Colombo, L.; Bisaha, J. J.; Clardy,
J.; Cherry, D. J. Am. Chem. Soc. 1992, 114, 5977-5985; Oppolzer, W.;
Froelich, O.; Wiaux-Zamar, C.; Bernardinelli, G. Tetrahedron Lett. 1997, 38,
2825-2828.
(7) (a) Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 12-13. (b) Lee,
Y.; Silverman, R. B. Org. Lett. 2000, 2, 303-306.
(8) Prakash, G. K. S., Mandal, M., Olah, G. A. Angew. Chem., Int. Ed.
2001, 40, 589-590.
(9) (a) Tang, T. P.; Volkman, S. K.; Ellman, J. A. unpublished results. (b)
Barrow, J. C.; Ngo, P. L.; Pellicore, J. M.; Selnick, H. G.; Nantermet, P. G.
Tetrahedron Lett. 2001, 42, 2051-2054.
(14) Racemic support-bound sulfinamide 1 may also readily be accessed
by addition of NH4OH to 4 to provide racemic 6 in 71% yield.
(15) Condensation of ketones with 1 has been accomplished using Ti(OEt)4
in THF at elevated temperatures.
(10) Sun, P.; Weinreb, S. M. J. Org. Chem. 1997, 62, 8604-8608.
(11) Woolard, F. X.; Paetsch, J.; Ellman, J. A. J. Org. Chem. 1997, 62,
6102-6103.
10.1021/ja016349j CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/20/2001

10128 J. Am. Chem. Soc., Vol. 123, No. 41, 2001
Communications to the Editor
Scheme 2a
Scheme 3a
a
Reagents and conditions: (a) RCHO, Ti(OEt)4, THF; (b) EtMgBr,
CH2Cl2, -48 °C; (c) 0.67 N HCl, 1:1 CH2Cl2/nBuOH.
Table 1. Solid-Phase Synthesis of R-Branched Amines
compound
R
% yielda
dr b
8a
8b
8c
8d
iPr
Ph
Bn
95
95
90
95
97:3 (97:3)
88:12 (92:8)
89:11 (92:8)
96:4 (99:1)
pMeOPh
a
Yields were determined via 1H NMR integration against an internal
b
standard. Numbers in parentheses represent solution-phase results.
a Reagents and conditions: (a) 3,4-(MeO)2PhCH2CHO, Ti(OEt)4, THF;
(b) 3-MeOPhMgBr, CH2Cl2, -48 °C; (c) KO-t-Bu, NMP, allyl bromide;
(d) m-CPBA, CH2Cl2/DMF; (e) 2.5% OsO4/t-BuOH, NMO, THF; (f)
Pb(OAc)4, 10:1 CH2Cl2/AcOH; (g) dil HCl, CH2Cl2; (h) 3:1 CH2Cl2/
HCO2H; (i) 0.1 N TfOH, 1,4-dimethoxybenzene, CH2Cl2; (j) sulfonic
acid resin then NH3/MeOH.
Figure 1. Pomeranz-Fritsch synthesis of pavine and isopavine alkaloids.
of the polystyrene support. Notably, amine hydrochlorides 8 were
obtained in near quantitative overall yields in three steps based
on the loading of brominated polystyrene. Furthermore, the %
ee of the products was only slightly lower than that observed for
the corresponding solution-phase synthesis (Table 1).
In the presence of dilute HCl in CH2Cl2 aldehyde 13 was
cyclized with complete selectiVity to the pavine derivative 14.
Similarly, isopavine alkaloid 16 was obtained with complete
selectiVity through formic acid-mediated cyclization.19 The final
free amine derivatives 15 and 17 were obtained in high purity20
without purification by cleavage from the solid phase using dilute
triflic acid in CH2Cl2 followed by neutralization and scavenging
with sulfonic acid resin.21 Over the eight-step sequence, 15 and
17 were obtained in 86:14 enantiomeric ratios and 45 and 47%
yields, respectively.
The efficient preparation of support-bound sulfinamide 1 was
accomplished using a dynamic resolution methodology to access
the key enantiomerically pure sulfinamide intermediate 6. Using
linker 1 chiral amines can be synthesized in near quantitative
yields and in good enantiomeric purities. Finally, the synthesis
of pavine and isopavine alkaloids demonstrates the utility of the
linker for the multistep asymmetric synthesis of natural product-
like compounds. Further applications of sulfinamide 1 will be
reported in due course.
To demonstrate the utility and versatility of 1, the syntheses
of the pavine and isopavine classes of alkaloids, 9 and 10, were
undertaken (Figure 1). These alkaloids have important and diverse
bioactivities. For example, pavine derivatives have been identified
that inhibit TNF-R production16 and isopavine derivatives are
potent PCP receptor ligands.17 We envisioned that diverse mem-
bers of both alkaloid classes could potentially be accessed from
the common intermediate 11 through modified Pomeranz-Fritsch
conditions.18 The R-branched amine present in 11 should be
accessible by addition of aryl Grignard reagents to support-bound
arylacetaldimines that may readily be accessed by condensation
of arylacetaldehydes and 1. Notably, due to competitive R-depro-
tonation, only one successful example of Grignard additions to
arylacetaldimines has been reported.5a
The synthesis was initiated by condensation of 3,4-dimethoxy-
phenylacetaldehyde with 1 using excess Ti(OEt)4 (Scheme 3).
Addition of 3-methoxyphenylmagnesium bromide provided the
desired amine 12, which could be cleaved from support in 75%
yield from bromopolystyrene. The sulfinyl nitrogen was then
allylated by deprotonation with KO-t-Bu followed by addition
of allyl bromide. The sulfinyl group was then oxidized to the
sulfonamide with m-CPBA to provide a linker that is stable to
subsequent acidic reaction conditions. Catalytic osmylation with
excess N-methylmorpholine N-oxide in THF provided the 1,2-
glycol, which was then cleaved with Pb(OAc)4 in 10:1 CH2Cl2/
acetic acid to give the aldehyde cyclization precursor 13.
Acknowledgment. This research was supported by the NSF. We thank
Dr. Derek Cogan for helpful advice. The Center for New Directions in
Organic Synthesis is supported by Bristol-Myers-Squibb as Sponsoring
Member.
Supporting Information Available: Synthetic procedures and char-
acterization of new compounds (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
JA016349J
(16) Fujiwara, N.; Ueda, Y.; Ohashi, N. Bioorg. Med. Chem. Lett. 1996,
6, 743-748.
(19) Yamada, K.; Takeda, M.; Itoh, N.; Ohtsuka, H.; Tsunashima, A.;
Iwakuma, T.; Chem. Pharm. Bull. 1982, 30, 3197-3201.
(17) Gee, K. R.; Barmettler, P.; Rhodes, M. R.; McBurney, R. N.; Reddy,
N. L.; Hu, L.-Y.; Cotter, R. E.; Hamilton, P. N.; Weber, E.; Keana, J. F. W.
J. Med. Chem. 1993, 36, 1938-1946.
(20) 1H NMR spectra of 15 and 17 obtained directly after cleavage from
resin are provided in the Supporting Information.
(21) Siegel, M. G.; Hahn, P. J.; Dressman, B. A.; Fritz, J. E.; Grunwell, J.
R.; Kaldor, S. W. Tetrahedron Lett. 1997, 38, 3357-3360.
(18) Gensler, W. J. Org. React. 1951, 6, 191-206.