Highly diastereoselective addition of alkynylmagnesium chlorides to N-tert-butanesulfinyl aldimines: A practical and general access to chiral α-branched amines

Article abstract of DOI:10.1021/jo902424m

(Chemical Equation Presented) The addition of alkynylmagnesium chlorides to N-tert-butanesulfinyl imines proceeded with a remarkably high diastereoselectivity (dr > 13:1, mostly diastereopure), and with a general scope of both reaction partners. The high dr translated into simplified purification and higher optical purity for the synthesis of a wide array of chiral R-branched amines. The alkyne functionality also provides a multitude of opportunities for further synthetic transformations. The short asymmetric synthesis of (+)-angustureine 7 and (-)-cuspareine 10 was realized with use of this approach.

Full text of DOI:10.1021/jo902424m

pubs.acs.org/joc
for the synthesis of chiral amines,1-4 thanks to the pioneer-
Highly Diastereoselective Addition of
Alkynylmagnesium Chlorides to N-tert-
Butanesulfinyl Aldimines: A Practical and General
Access to Chiral r-Branched Amines
ing work of Davis, Ellman, and colleagues.5 However, it
should be noted that the level of asymmetric induction via
this approach is not always perfect. A careful literature
survey revealed that the diastereoselectivity is highly depen-
dent on the nature of the imine C-appendage R, the incoming
group R0, the metal countercation, the solvent and the
additive. The lack of highly stereoselective preparation
methods for some important types of chiral R-branched
amines, such as 1-aryl-1-alkyl carbinamines and Z-allylic
amines, is conspicuous and needs effective solutions. More
importantly, the separation of diastereomeric products by
conventional methods (flash chromatography or recrystalli-
zation) is not always possible in practice, often due to
identical chromatographic behavior or undesirable physical
properties. In these cases, the lower dr value is inevitably
carried forward to the final products which, after removal of
the chiral sulfinyl group, exhibit lower er values. Therefore, a
high dr not only enhances the yield, but facilitates purifica-
tion, especially on large scales. Prompted by the significance
of chiral propargylic amines,6,7 we see the addition of alkynyl
Grignard reagents to t-BS imines not only as an access to this
structural unit itself, but the solution to many other types of
synthetically challenging chiral N-secondary alkyl amines
(Figure 1). Interestingly, such alkynyl addition has not
received its due attention, except that the Ellman group
reported the addition to ketimines, using AlMe3 as a man-
datory additive,8a whereas Hou and co-workers investigated
Bai-Ling Chen,† Bing Wang,*,†,‡ and Guo-Qiang Lin†,‡
†Department of Chemistry, Fudan University, 220 Handan
Road, Shanghai 200433, China and Institutes of Biomedical
‡
Sciences, Fudan University, 138 Yixueyuan Road,
Shanghai 200032, China
wangbing@fudan.edu.cn
Received November 12, 2009
The addition of alkynylmagnesium chlorides to N-tert-
butanesulfinyl imines proceeded with a remarkably high
diastereoselectivity (dr>13:1, mostly diastereopure), and
with a general scope of both reaction partners. The high
dr translated into simplified purification and higher
optical purity for the synthesis of a wide array of chiral
R-branched amines. The alkyne functionality also provides
a multitude of opportunities for further synthetic trans-
formations. The short asymmetric synthesis of (+)-an-
gustureine 7 and (-)-cuspareine 10 was realized with use
of this approach.
(5) For reviews, see: (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc.
Chem. Res. 2002, 35, 984. (b) Lin, G.-Q.; Xu, M.-H.; Zhong, Y.-W.; Sun,
X.-W. Acc. Chem. Res. 2008, 41, 831. (c) Ferreira, F.; Botuha, C.; Chemla, F.;
ꢀ
Perez-Luna, A. Chem. Soc. Rev. 2009, 38, 1162. (d) Morton, D.; Stockman,
R. A. Tetrahedron 2006, 62, 8869. (e) Davis, F. A.; Zhou, P.; Chen, B. C.
Chem. Soc. Rev. 1998, 27, 13.
(6) Selected synthetic approaches to chiral propargylic amines: (a)
Huffman, M. A.; Yasuda, N.; DeCamp, A. E.; Grabowski, E. J. J. J. Org.
Chem. 1995, 60, 1590. (b) Fischer, C.; Carreira, E. M. Org. Lett. 2001, 3, 4319.
(c) Li, C.-J.; Wei, C. Chem. Commun. 2002, 268. (d) Wei, C.; Li, C.-J. J. Am.
Chem. Soc. 2002, 124, 5638. (e) Traverse, J. F.; Hoveyda, A. H.; Snapper, M.
L. Org. Lett. 2003, 5, 3273. (f) Fischer, C.; Carreira, E. M. Org. Lett. 2004, 6,
1497. (g) Wei, C.; Mague, J. T.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5749. (h) Gommermann, N.; Knochel, P. Chem. Commun. 2004, 2324.
(i) Turcaud, S.; Berhal, F.; Royer, J. J. Org. Chem. 2007, 72, 7893. (j) Bishop,
J. A.; Lou, S.; Schaus, S. E. Angew. Chem., Int. Ed. 2009, 48, 4337. For
reviews, see: (k) Wei, C.; Li, Z.; Li, C.-J. Synlett 2004, 1472. (l) Reginato, R.;
Meffre, P.; Gaggini, F. Amino Acids 2005, 29, 81. (m) Zani, L.; Bolm, C.
Chem. Commun. 2006, 4263. (n) Trost, B. M.; Weiss, A. H. Adv. Synth. Catal.
2009, 351, 963.
Nucleophilic additions to N-tert-butanesulfinyl (t-BS
hereafter) imines constitute an immensely useful strategy
(7) For recent applications, see: (a) Cantel, S.; Isaad, A. L. C.; Scrima,
M.; Levy, J. J.; DiMarchi, R. D.; Rovero, P.; Helperin, J. A.; D’Ursi, A. M.;
Papini, A. M.; Chorev, M. J. Org. Chem. 2008, 73, 5663. (b) Lo, V. K.-Y.;
Zhou, C.-Y.; Wong, M.-K.; Che, C.-M. Chem. Commun. 2010, 46, 213. For a
review on click chemistry, see: (c) Kolb, H. C.; Finn, M. G.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2001, 40, 2004.
(8) Addition of alkynyllithium: (a) Patterson, A. W.; Ellman, J. A. J. Org.
Chem. 2006, 71, 7110 (ketimines). (b) Ding, C.-H.; Chen, D.-D.; Luo, Z.-B.; Dai,
L.-X.; Hou, X.-L. Synlett 2006, 1272 (addition to racemic substrates, 88-95%
de). (c) Chen, X.-Y.; Qiu, X.-L.; Qing, F.-L. Tetrahedron 2008, 64, 2301
(trifluoromethylacetylide, 72-98% de). Hypervalent silicon species: (d) Letten,
R. B., II; Scheidt, K. A. Org. Lett. 2005, 7, 3227 (one example, 90% de).
Alkynylcerium reagent: (e) Hodgson, D. M.; Kloesges, J.; Evans, B. Org. Lett.
2008, 10, 2781 (one example, 70% de). Widely variable diastereoselectivities
were obtained in previous reports using alkynylmagnesium bromide: (f) Barrow,
J. C.; Ngo, P. L.; Pellicore, J. M.; Selnick, H. G.; Nantermet, P. G. Tetrahedron
Lett. 2001, 42, 2051 (one example, 54% de). (g) Reference 1d (one example, 80% de).
(h) Kuduk, S. D.; DiPardo, R. M.; Chang, R. K.; Ng, C.; Bock, M. G. Tetrahedron
Lett. 2004, 45, 6641 (one example, 90% de).
(1) For addition of carbanions, see: (a) Liu, G.; Cogan, D. A.; Ellman, J. A.
J. Am. Chem. Soc. 1997, 119, 9913. (b) Cogan, D. A.; Liu, G.; Ellman, J. A.
Tetrahedron 1999, 55, 8883. (c) Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc.
1999, 121, 268. (d) Tang, T. P.; Volkman, S. K.; Ellman, J. A. J. Org. Chem.
2001, 66, 8772. (e) Evans, J. W.; Ellman, J. A. J. Org. Chem. 2003, 68, 9948.
(f) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Angew. Chem., Int. Ed. 2001, 40,
589. (g) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Org. Lett. 2001, 3, 2847.
(2) For addition of enolates, see: (a) Tang, T. P.; Ellman, J. A. J. Org.
Chem. 1999, 64, 12. (b) Tang, T. P.; Ellman, J. A. J. Org. Chem. 2002, 67,
7819. (c) Reference 1e. (d) Wang, Y.; He, Q.-F.; Wang, H.-W.; Zhou, X.; Huang,
Z.-Y.; Qin, Y. J. Org. Chem. 2006, 71, 1588.
(3) For additions of organoboron species, see: (a) Weix, D. J.; Shi, Y.;
Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 1092. (b) Dai, H.; Lu, X. Org. Lett.
2007, 9, 3077. (c) Bennen, M. A.; An, C.; Ellman, J. A. J. Am. Chem. Soc. 2008,
130, 6910. (d) Brak, K.; Ellman, J. A. J. Am. Chem. Soc. 2009, 131, 3850.
(4) For reduction of ketimines, see: (a) Borg, G.; Cogan, D. A.; Ellman,
J. A. Tetrahedron Lett. 1999, 40, 6709. (b) Colyer, J. T.; Andersen, N. G.;
Tedrow, J. S.; Soukup, T. S.; Faul, M. M. J. Org. Chem. 2006, 71, 6859.
DOI: 10.1021/jo902424m
r
Published on Web 12/31/2009
J. Org. Chem. 2010, 75, 941–944 941
2009 American Chemical Society

Chen et al.
JOCNote
TABLE 1. Comparison of the Stereoselectivity of Carbanion Additions
to t-BS aldimine 1aa
FIGURE 1. Proposed solutions to some synthetically challenging
chiral N-secondary alkyl amines.
the addition of alkynyllithiums.8b As the continuation of our
interest in the chemistry of N-tert-butanesulfinimine,9 herein
we report the details of a study on the alkynyl Grignard
addition to N-t-BS aldimines.
Addition of representative Grignard reagents to aldimine
1a under literature conditions afforded the expected adducts
1
in modest to very good yields (entries 1-5). However, H
NMR of the purified products showed that significant
amounts of diastereomers were present, which could not be
separated by flash chromatography. After removal of the
t-BS auxiliary from 2a-c and derivatization, chiral HPLC
analysis of the N-methyl carbamates revealed that the ee
values of the R-branched amines were unsatisfactory, ran-
b
c
aAll reactions run on 0.5-1.0 mmol scales. Isolated yields. Enan-
tiomeric excess of N-methyl carbamate derivatives of the crude adducts,
determined by chiral HPLC, see the Supporting Information. dInsepar-
able diastereomers. eAlMe3 as the additive.
8a
ging from 77% to 92%. Using AlMe3 as an additive
TABLE 2. Highly Diastereoselective Addition of Alkynylmagnesium
improved the dr only marginally in the case of phenyl
addition (entry 3). On the other hand, the addition of alkynyl
magnesium chlorides to 1a resulted in good to very good
yields and excellent diastereoselectivity (entries 6, 8, and 9).
The reaction of commercial ethynylmagnesium bromide was
complicated by proton exchange of the normal adduct 2f
with the excess reagent and further coupling with 1a. For-
tunately, this was remedied by using the readily removable
trimethylsilyl to block the other end of ethynyl (entry 8).
This protocol turned out to cover a wide substrate scope
(Table 2). Various C-alkyl, C-aryl, and C-heteroaryl N-tert-
butanesulfinyl aldimines underwent smooth Grignard addi-
tions to afford the desired N-t-BS propargylic amines. The
highly hindered imine 3b and the R-oxygenated substrate 3c
were both suitable electrophiles (entries 4-9). 4-Nitroben-
zaldehyde-derived t-BS imine 3f also gave adducts 4fB and
4fC in decent yields, which in our hands were inaccessible via
the analogous addition of alkynyllithiums.8b Meanwhile,
electron-rich imine 3g was less reactive, only the addition
of 2-TMS-ethynyl was feasible (entry 17). Nevertheless,
removal of TMS followed by Sonogashira coupling would
allow further elaboration of the other end of the triple bond.
The yields for heteroaromatic aldimines 3i, 3j, and 3k were
modest (30-70%); however, in view of the presence of
adjacent heteroatoms capable of chelation to metal counter-
cations, the high dr values were notable. Among the 28
examples listed in Tables 1 and 2, only four (4eA, 4eB,
4eC, and 4jC) exhibited slightly lower dr values (13-25:1),
in all other cases the adducts were virtually diastereopure. In
addition, all four diastereomeric pairs are separable on silica
gel column, suggesting the beneficial influence of the alkynyl
group on product separation. The imine derived from pyr-
role-2-carboxaldehyde did not react under this protocol,
probably due to the unprotected acidic N-H or the electro-
nic effects. The effect of the nucleophile structure was more
Chlorides to N-tert-Butanesulfinyl Aldiminesa
b
aAll reactions run on 0.5-1.0 mmol scales. Isolated yields of pure
diastereomers. Distereoselectivity determined by 1H NMR of the crude
adducts. cSeparable diastereomers.
subtle, the yields for phenylethynyl adducts were usually
lower than those of alkyl- or silylethynyl analogues, with
more side products.
(9) (a) Wang, B.; Wang, Y.-J. Org. Lett. 2009, 11, 3410. (b) Wang, B.; Liu,
R.-H. Eur. J. Org. Chem. 2009, 2845. (c) Liu, R.-H.; Fang, K.; Wang, B.; Xu,
M.-H.; Lin, G.-Q. J. Org. Chem. 2008, 73, 3307.
942 J. Org. Chem. Vol. 75, No. 3, 2010

Chen et al.
JOCNote
The absolute configuration of adduct 4aB was established
by single-crystal X-ray analysis, which showed that RS-imine
produced (RS,R)-adduct (see the Supporting Information for
the ORTEP plot). Other representative adducts (4cC, 4dC,
and 4iA) were also correlated with known compounds for
unambiguous determination of stereochemistry (see the
Supporting Information). Thus, the sense of chiral induction
was the same as that of the addition of lithioalkynes,8b
although the reaction conditions was quite different with
regard to the solvent, metal countercation, and temperature.
Moreover, alkynyl Grignard reagents afforded generally
higher dr (mostly diastereopure) than their lithium counter-
parts (88-95% de).
SCHEME 1. Short Asymmetric Synthesis of (+)-Angustureine
and ( )-Cuspareine
9
With this protocol in hand, we applied it to the asymmetric
synthesis of two chiral 2-substituted tetrahydroquinoline10
alkaloids, namely, angustureine11 and cuspareine.12 Satura-
tion of the triple bond of 2h afforded 5 in very good yield. By
using the classic Pd-catalyzed Buchwald-Hartwig amina-
tion reaction,13 the free amine 6 was obtained in 63% yield.
It was noteworthy that the t-BS auxiliary was concomitantly
removed from the aniline nitrogen under basic condi-
tions. Analogous intramolecular amination with CuI as
the catalyst did not work, and 5 was recovered. Reductive
N-methylation afforded the target molecule (+)-7, the anti-
pode of the natural product, in excellent yield (41% overall
yield from 1a). In a similar vein, the native (-)-cuspareine
(10) was prepared in a short six-step sequence from imine 1a
and the readily available (3,4-dimethoxyphenyl)ethyne,14
with an overall yield of 24% (Scheme 1).
SCHEME 2. Synthesis of 2-Z-Alkenyl tetrahydroquinolines
Moreover, the propargylic adducts are also ideal building
blocks for the synthesis of Z-allylic amines which were
otherwise difficult to access. In this connection, the t-BS
group was first replaced by Boc, partial hydrogenation of
alkyne 11 using Lindlar’s catalyst established the cis config-
uration of 12, and the latter underwent Pd-catalyzed intra-
molecular amination smoothly to afford 2-Z-alkenyl
tetrahydroquinoline 13 in 64% yield (Scheme 2). Under the
same conditions, the N-t-BS analogue of 12 could also cyclize
to give tetrahydroquinoline, however, in a diminished yield
(34%). This approach complemented the iridium-catalyzed
asymmetric hydrogenation of quinolines10 in that the olefin
in the side chain could be tolerated.
(10) Asymmetric hydrogenation leading to 2-substituted tetrahydroqui-
nolines: (a) Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou, Y.-G.
J. Am. Chem. Soc. 2003, 125, 10536. (b) Lu, S.-M.; Wang, Y.-Q.; Han, X.-W.;
Zhou, Y.-G. Angew. Chem., Int. Ed. 2006, 45, 2260. (c) Wang, X.-B.; Zhou,
Y.-G. J. Org. Chem. 2008, 73, 5640. (d) Wang, X.-B.; Wang, D.-W.; Lu,
S.-M.; Yu, C.-B.; Zhou, Y.-G. Tetrahedron: Asymmetry 2009, 20, 1040.
(e) Wang, D.-W.; Wang, X.-B.; Lu, S.-M.; Yu, C.-B.; Zhou, Y.-G. J. Org.
Chem. 2009, 74, 2780. (f) Wang, C.; Li, C.; Wu, X.; Pettman, A.; Xiao, J.
Angew. Chem., Int. Ed. 2009, 48, 6524. (g) Tadaoka, H.; Cartigny, D.;
^
Nagano, T.; Gosavi, T.; Ayad, T.; Genet, J.-P.; Ohshima, T.; Ratoveloma-
In conclusion, we have demonstrated that the addition of
alkynylmagnesium chlorides to t-BS imines proceeded in a
highly diastereoselective manner (dr > 13:1), without the
need of additives. The propargylic adducts are versatile
intermediates for the syntheses of natural products and
synthetically challenging chiral N-secondary alkyl amines.
The short asymmetric synthesis of two representative 2-
substituted tetrahydroquinoline alkaloids 7 and 10 were
realized. Unexpected deblocking of t-BS auxiliary from ani-
line nitrogen under basic conditions was encountered. This
sulfinimine-based approach is synthetically useful for its
wide scope in both the imine and the nucleophile, consis-
tently high stereoselectivity, and easy separation of diaster-
eomeric adducts.
nana-Vidal, V.; Mashima, K. Chem.;Eur. J. 2009, 15, 9990. For an
excellent review, see: (h) Zhou, Y.-G. Acc. Chem. Res. 2007, 40, 1357.
(11) Isolation of angustureine: (a) Jacquemond-Collet, I.; Hannedouche,
ꢀ
S.; Fabre, N.; Fouraste, I.; Moulis, C. Phytochemistry 1999, 51, 1167.
Asymmetric synthesis of 7: (b) References 10a and 10b. (c) Theeraladanon,
C.; Arisawa, M.; Nakagawa, M.; Nishida, A. Tetrahedron: Asymmetry 2005,
16, 827. (d) Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew. Chem.,
Int. Ed. 2006, 45, 3683. (e) Wang, Z.-J.; Zhou, H.-F.; Wang, T.-L.; He, Y.-M.;
Fan, Q.-H. Green Chem. 2009, 11, 767. Synthesis of racemic 7: (f) Shahane,
S.; Louafi, F.; Moreau, J.; Hurvois, J.-P.; Renaud, J.-L.; van der Weghe, P.;
Roisnel, T. Eur. J. Org. Chem. 2008, 4622. (g) O’Byrne, A.; Evans, P.
Tetrahedron 2008, 64, 8067. (h) Kothandaraman, P.; Foo, S. J.; Chan,
P. W. H. J. Org. Chem. 2009, 74, 5947. (i) Patil, N. T.; Wu, H.; Yamamoto,
€
Y. J. Org. Chem. 2007, 72, 6577. (j) Avemaria, F.; Vanderheiden, S.; Brase, S.
Tetrahedron 2003, 59, 6785.
(12) Isolation of cuspareine: (a) Rakotoson, J. H.; Fabre, N.; Jacque-
ꢀ
mond-Collet, I.; Hannedouche, S.; Fouraste, I.; Moulis, C. Planta Med.
1998, 64, 762. Asymmetric synthesis of 10: (b) References 10a, 10b, and 11d.
Synthesis of racemic 10: (d) References 11f and 11g.
(13) For reviews on the Buchwald-Hartwig amination, see: (a) Wolfe,
J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31,
805. (b) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852. (c) Hartwig, J. F.
Angew. Chem., Int. Ed. 1998, 37, 2046. (d) Buchwald, S. L.; Muci, A. Top.
Curr. Chem. 2002, 219, 133.
Experimental Section
General Procedure. To a cooled (-78 °C) solution of sulfiny-
limine (1.0 mmol) in CH2Cl2 (5 mL) under Ar was added drop-
wise the freshly prepared alkynyl Grignard reagent (2-3 mmol
(14) Fang, Z.; Song, Y.; Sarkar, T.; Hamel, E.; Fogler, W. E.; Agoston,
G. E.; Fanwick, P. E.; Cushman, M. J. Org. Chem. 2008, 73, 4241.
J. Org. Chem. Vol. 75, No. 3, 2010 943

Chen et al.
JOCNote
in THF/ether), and the solution was stirred at the same tem-
perature for 2 h, then gradually warmed to room temperature
and stirred overnight. The reaction was quenched by sat. aq
NH4Cl then extracted by EtOAc, and the combined organic
phase was washed with brine, dried (NaSO4), and concentrated
under reduced pressure. The residue was purified by silica gel
flash column chromatography eluted with EtOAc/hexane.
Compound 2h: [R]28D -33.6 (c 0.50, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.52 (d, 1H, J = 7.8 Hz), 7.25-7.21 (m, 2H),
7.09-7.04 (m, 1H), 4.14-4.07 (m, 1H), 3.37 (d, 1H, J = 5.8 Hz),
2.96-2.85 (m, 2H), 2.21 (td, 2H, J = 7.0, 2.1 Hz), 2.04-1.94 (m,
2H), 1.55 (sextet, 2H, J = 7.2 Hz), 1.23 (s, 9H), 1.00 (t, 3H, J =
7.3 Hz). 13C NMR (125 MHz, CDCl3) δ 140.6, 132.8, 130.4,
127.7, 127.5, 124.3, 85.9, 79.5, 55.9, 47.5, 37.1, 32.3, 22.5, 22.0,
20.7, 13.5. HR-ESI-MS m/z calcd for C18H27BrNOS (M + H+)
384.0997, found 384.0975.
HR-ESI-MS m/z calcd for C15H24N (M + H+) 218.1909, found
218.1892.
Adduct 2i (260 mg, 0.54 mmol) dissolved in MeOH (2 mL)
was treated with 2 M HCl-MeOH (0.4 mL) at rt for 4 h, the
volatiles were removed under reduced pressure, then to the
residue was added DCM (5 mL), NaHCO3 (90 mg, 1.08 mmol),
and Boc2O (175 mg, 0.80 mmol). The mixture was stirred at rt
overnight, diluted with DCM, filtered, and concentrated. The
residue was purified by column chromatography (hexane/
EtOAc = 1/10) to afford 8 (224 mg, 87%).
Compound 8: [R]25 -3.5 (c 0.37, CHCl3); H NMR (500
1
D
MHz, CDCl3) δ 7.52 (d, 1H, J = 8.0 Hz), 7.27 (dd, 1H, J = 7.5,
1.5 Hz), 7.23 (td, 1H, J = 7.5, 1.0 Hz), 7.08-7.01 (m, 2H), 6.94
(d, 1H, J = 2.0 Hz), 6.79 (d, 1H, J = 8.5 Hz), 4.91 (s br, 1H), 4.71
(s br, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.01-2.89 (m, 2H),
2.09-2.02 (m, 2H), 1.47 (s, 9H); 13C NMR (125 MHz, CDCl3)
δ 154.8, 149.5, 148.5, 140.5, 132.8, 130.4, 127.7, 127.5, 124.9,
124.4, 114.8, 114.4, 110.9, 86.7, 83.5, 79.8, 55.8, 43.2, 36.4, 32.4,
28.3; HR-ESI-MS m/z calcd for C24H28BrNNaO4 (M + Na+)
496.1099, found 496.1130.
A suspension of 2h (104 mg, 0.27 mmol) and PtO2 (5 mg) in
EtOH (3 mL) was stirred under H2 atmosphere (1 atm) for
5 h, the solvent was removed under reduced pressure, and the
residue was purified by column chromatography (EtOAc/
hexane = 1/4) to afford 5 (84 mg, 80%).
Conversion of 8 to 9 followed the procedure for 2h to 6. To a
solution of 9 (50 mg, 0.12 mmol) in THF (10 mL) was added
LiAlH4 (30 mg, 0.79 mmol) under rt, and the mixture was
refluxed for 5 h, cooled to 0 °C, quenched by several drops of
water, and basified by 10% NaOH. The mixture was extracted
with ether (3 ꢀ 20 mL), then the combined organic phase was
dried over K2CO3 and concentrated. The residue was purified by
column chromatography (EtOAc/hexane = 1/6) to afford 10
(28 mg, 75%).
1
Compound 5: [R]27 -23.8 (c 0.40, CHCl3); H NMR (500
D
MHz, CDCl3) δ 7.52 (d, 1H, J = 7.8 Hz), 7.26-7.18 (m, 2H),
7.08-7.03 (m, 1H), 3.34-3.27 (m, 1H), 3.07 (d, 1H, J = 6.8 Hz),
2.89 (ddd, 1H, J = 13.0, 11.0, 4.5 Hz), 2.70 (ddd, 1H, J = 13.0,
11.0, 5.5 Hz), 1.90-1.81 (m, 1H), 1.76-1.57 (m, 3H), 1.45-1.35
(m, 2H), 1.35-1.27 (m, 4H), 1.25 (s, 9H), 0.88 (t, 3H, J = 6.9
Hz); 13C NMR (125 MHz, CDCl3) δ 141.4, 132.8, 130.2, 127.6,
127.5, 124.3, 56.6, 55.8, 36.4, 35.8, 32.4, 31.7, 25.3, 22.7, 22.5,
14.0; HR-ESI-MS m/z calcd for C18H31BrNOS (M + H+)
388.1310, found 388.1339.
(-)-Cuspareine 10: [R]25D -30.3 (c 0.27, CHCl3); {lit.: [R]25
D
-22.8 (c 1.00, CHCl3),12a [R]25D -30.2 (c 0.95, CHCl3)10b}; 1H
NMR (500 MHz, CDCl3) δ 7.08 (t, 1H, J = 7.7 Hz), 6.98 (d, 1H,
J = 7.2 Hz), 6.78 (d, 1H, J = 8.0 Hz), 6.74-6.69 (m, 2H), 6.59
(t, 1H, J = 7.0 Hz), 6.53 (t, 1H, J = 7.8 Hz), 3.86 (s, 3H), 3.85
(s, 3H), 3.32-3.25 (m, 1H), 2.91 (s, 3H), 2.89-2.81 (m, 1H),
2.73-2.63 (m, 2H), 2.57-2.49 (m, 1H), 1.99-1.87 (m, 3H),
1.77-1.69 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 149.0, 147.3,
145.3, 134.6, 128.6, 127.1, 121.8, 120.1, 115.4, 111.7, 111.4,
110.6, 58.4, 56.0, 55.9, 38.1, 33.1, 31.9, 24.4, 23.6; HR-ESI-MS
m/z calcd for C20H26NO2 (M + H+) 312.1964, found 312.1962.
Under Ar atmosphere, a mixture of 5 (107 mg, 0.27 mmol),
Pd(OAc)2 (2.0 mg, 3.3 mmol %), rac-BINAP (8.0 mg, 5 mol %),
and Cs2CO3 (123 mg, 1.4 equiv) in toluene (2 mL) was heated at
100 °C overnight, cooled, and concentrated. The residue was
purified by column chromatography (EtOAc/hexane = 1/20) to
afford 6 (36 mg, 63%). The aniline 6 was dissolved in MeCN
(3 mL), to the solution was added sequentially 30% aq CH2O
(0.4 mL), NaBH3CN (95 mg, 1.53 mmol), and HOAc (0.1 mL),
then additional HOAc (0.1 mL) was added after 30 min; after
full conversion of the starting material (1 h), the mixture was
diluted with ether (30 mL), washed with 1 M KOH (3 ꢀ 5 mL),
dried over K2CO3, and concentrated. The residue was purified
by column chromatography (hexane) to afford 7 (37 mg, 96%).
Acknowledgment. Funding from the National Natural
Science Foundation of China (Nos. 20832005 and
20602008) and Fudan University (Nos. EYH1615003 and
EYH1615004) is gratefully acknowledged. B.W. thanks the
Institutes of Biomedical Sciences for an open funding.
(+)-Angustureine 7: [R]24D +9.50 (c 0.40, CHCl3) {lit.: [R]D
-7.16 for enantiomer,11a [R]23 +7.9 (c 1.00, CHCl3)11c}; H
1
D
NMR (500 MHz, CDCl3) δ 7.10 (t, 1H, J = 7.5 Hz), 6.96 (d, 1H,
J = 7.2 Hz), 6.62-6.48 (m, 2H), 3.26-3.19 (m, 1H), 2.92 (s, 3H),
2.84-2.75 (m, 1H), 2.68-2.61 (m, 1H), 1.92-1.85 (m, 2H),
1.65-1.54 (m, 1H), 1.43-1.22 (m, 7H), 0.89 (t, 3H, J = 6.8 Hz);
13C NMR (125 MHz, CDCl3) δ 145.4, 128.6, 127.0, 121.9,
115.2, 110.4, 59.0, 37.9, 32.0, 31.3, 25.7, 24.5, 23.6, 22.6, 14.0;
Supporting Information Available: Characterization data,
1H and 13C NMR spectra for all new compounds, and crystal-
lographic data for 4aB (CIF file). This material is available free
of charge via the Internet at http://pubs.acs.org.
944 J. Org. Chem. Vol. 75, No. 3, 2010