Highly regio- and enantioselective catalytic hydrogenation of enamides in conjugated diene systems: Synthesis and application of γ,δ-unsaturated amino acids

Article abstract of DOI:10.1021/ja9731074

An extremely efficient method has been found for the catalytic asymmetric hydrogenation of conjugated α,γ-dienamide esters using the Et-DuPHOS-Rh catalyst system. α,γ-Dienamide ester substrates were prepared via the Suzuki cross-coupling reaction and the

Full text of DOI:10.1021/ja9731074

J. Am. Chem. Soc. 1998, 120, 657-663
657
Highly Regio- and Enantioselective Catalytic Hydrogenation of
Enamides in Conjugated Diene Systems: Synthesis and Application
of γ,δ-Unsaturated Amino Acids
,†
‡
Mark J. Burk,* John G. Allen, and William F. Kiesman
Contribution from the Department of Chemistry, Duke UniVersity, P. M. Gross Chemical Laboratory,
Durham, North Carolina 27708
X
ReceiVed September 3, 1997
Abstract: An extremely efficient method has been found for the catalytic asymmetric hydrogenation of
conjugated R,γ-dienamide esters using the Et-DuPHOS-Rh catalyst system. R,γ-Dienamide ester substrates
were prepared via the Suzuki cross-coupling reaction and the Horner-Emmons olefination. Full conversion
to the corresponding γ,δ-unsaturated amino acids with very high regio- and enantioselectivity was achieved
after short reaction times. This new methodology was applied to the synthesis of the natural product bulgecinine
from a prochiral dienamide ester.
Unsaturated amino acids are an important class of natural
products that display an array of interesting biological proper-
bond has been attributed to the ability of this group to chelate
to the catalyst metal center; this property is also believed to be
critical for attainment of high enantioselectivity in rhodium-
1
ties. Specifically, γ,δ-unsaturated amino acids not only have
2
6
been synthetically challenging targets but also have been
catalyzed hydrogenation reactions. To the best of our knowl-
3
isolated from a variety of natural sources and have served as
edge no attempts have been made to reduce conjugated enamido
esters. We now have developed a procedure that takes
advantage of this feature and herein describe the hydrogenation
of R,γ-dienamide esters to afford γ,δ-unsaturated amino acids
with both high regioselectivity and high enantioselectivity. A
demonstration of the use of this catalytic asymmetric method
in the synthesis of the natural product (+)-bulgecinine is also
included.
intermediates in the synthesis of complex amino acids and
peptides.4
We recently have shown that Rh complexes bearing DuPHOS
and BPE ligands are extremely effective catalysts in enantiose-
lective hydrogenation of a variety of prochiral unsaturated
substrates including enamide esters.5 In work with enamido
olefins it was demonstrated that an enamide double bond could
be hydrogenated with complete regioselectivity over distal CdC
5a
double bonds. The enhanced reactivity of the enamide double
†
Present address: Chiroscience Limited, Cambridge Science Park, Milton
Road, Cambridge, England CB4 4WE.
‡
Present address: Biogen Inc., 14 Cambridge Center, Cambridge, MA
0
2142.
X
Abstract published in AdVance ACS Abstracts, December 15, 1997.
1) (a) Shimohigashi, Y; English, M. L.; Stammer, C. H.; Costa, T.
(
Biochem. Biophys. Res. Commun. 1982, 104, 583-590. (b) Jung, G. Angew.
Chem., Int. Ed. Engl. 1991, 30, 1051. (c) Freud, S.; Jung, G.; Gutbrod, O.;
Folkers, G.; Gibbons, W. A.; Allgaier, H.; Werner, R. Biopolymers 1991,
3
1, 803. (d) Jain, R.; Chauhan, V. S. Biopolymers 1996, 40, 105.
2) (a) Mooier, H. H.; Hiemstra, H.; Speckamp, W. N. Tetrahedron 1989,
5, 4627. (b) Guo, Z.; Schaeffer, M. J.; Taylor, R. J. K. J. Chem. Soc.,
(
Results and Discussion
4
Chem. Commun. 1993, 874. (c) Leanna, M. R.; Morton, H. E. Tetrahedron
Lett. 1993, 4485. (d) Crisp, G. T.; Glink, P. T. Tetrahedron 1994, 50, 2623.
Substrate Preparation. Parallel synthetic routes were
developed for the preparation of the R,γ-dienamide ester
substrates 1. Suzuki cross-coupling (route A) of (Z)-methyl
(
e) Kazmaier, U.; Maier, S. Tetrahedron 1996, 52, 941.
3) (a) Drinkwater, D. J.; Smith, P. W. G. J. Chem. Soc. (C) 1971, 1305.
b) Letham, D. S.; Young, H. Phytochemistry 1971, 10, 23. (c) Davis, A.
(
7
(
2-acetamido-3-bromoacrylate (3) with a variety of vinyl boronic
L.; Cavitt, M. B.; McCord, T. J.; Vickrey, P. E.; Shive, W. J. Am. Chem.
Soc. 1973, 95, 6800. (d) Gellert, E.; Halpern, B.; Rudzats, R. Phytochemistry
(5) (a) Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am.
Chem. Soc. 1993, 115, 10125. (b) Burk, M. J.; Gross, M. F.; Harper, G. P.;
Kalberg, C. S.; Lee, J. R.; Martinez, J. P. Pure Appl. Chem. 1996, 68, 37.
(c) Burk, M. J.; Gross, M. F.; Martinez, J. P. J. Am. Chem. Soc., 1995,
117, 9375. (d) Burk, M. J.; Martinez, J. P.; Feaster, J. E.; Cosford, N.
Tetrahedron 1994, 50, 4399.
1
1
978, 17, 802. (e) Cramer, U.; Rehfeldt, A. G.; Spener, F. Biochemistry
980, 19, 3074. (f) Baldwin, J. E.; Adlington, R. M.; Basak, A. J. Chem.
Soc., Chem. Commun. 1984, 1284. (g) Tsubotani, S.; Funabashi, Y.;
Takamoto, M.; Hakoda, S.; Harada, S. Tetrahedron 1991, 47, 8079.
(4) (a) Bartlett, P. A.; Tanzella, D. J.; Barstow, J. F. Tetrahedron Lett.
1
6
6
7
7
982, 619. (b) Kurokawa, N.; Ohfune, Y. J. Am. Chem. Soc. 1986, 108,
041. (c) Ohfune, Y.; Hori, K.; Sakaitani, M. Tetrahedron Lett. 1986, 27,
079. (d) Madau, A.; Porzi, G.; Sandri, S. Tetrahedron: Asymmetry 1996,
, 825. (e) Graziani, L.; Porzi, G.; Sandri, S. Tetrahedron: Asymmetry 1996,
, 1341. (f) Wang, Y.-F.; Izawa, T.; Kobayashi, S.; Ohno, M. J. Am. Chem.
(6) (a) Halpern, J. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: New York, 1985; Vol. 5, Chapter 2. (b) Landis, C. R.;
Halpern, J. J. Am. Chem. Soc. 1987, 109, 1746. (c) Ojima, I.; Kogure, T.;
Yoda, N. J. Org. Chem. 1980, 45, 4728. (d) Nagel, U.; Rieger, B.
Organometallics 1989, 8, 1534. (e) Brown, J. M.; Chaloner, P. A. J. Chem.
Soc., Chem. Commun. 1980, 344. (f) Brown, J. M.; Murrer, B. A. J. Chem.
Soc., Perkin Trans. 2 1982, 489. (g) Chan, A. S. C.; Pluth, J. J.; Halpern,
J. J. Am. Chem. Soc. 1980, 102, 5952.
Soc. 1982, 104, 6465. (g) Takano, S.; Iwabuchi, Y.; Ogasawara, K. J. Chem.
Soc., Chem. Commun. 1988, 1527. (h) Hirai, Y.; Terada, T.; Amemiya, Y.;
Momose, T. Tetrahedron Lett. 1992, 33, 7893.
S0002-7863(97)03107-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/16/1998

658 J. Am. Chem. Soc., Vol. 120, No. 4, 1998
Burk et al.
Scheme 1
Table 1. Results of the Preparation of 1 by the Suzuki
Cross-Coupling Reactions
acids 4 furnished dienamide esters in good yields (Scheme 1).8
The mild reaction conditions (10 mol % Pd(OAc)2, Na2CO3,
9
5% EtOH at 50 °C) not only left the ester intact but also gave
the cross-coupling product with complete retention of config-
uration about both CdC double bonds. Two limitations of this
route were evident. The production of the boronic acids via
Brown’s hydroboration of alkynes limited us to trans-terminal
(
R′ ) H) and symmetrically (R′ ) R) substituted vinyl boronic
9
acids. Also, due to functional group incompatibilities, some
substituted boronic acids were not accessible.
Horner-Emmons olefination10 (route B) served as an alterna-
tive to the cross-coupling. The olefination reaction between
phosphonate 5 and a series of unsaturated aldehydes 6 proceeded
in THF at -78 °C f rt with tetramethylguanidine to give (Z)-
dienamide esters in fair yields.11 A greater diversity of
functionalized dienamide esters could be made in this manner,
but yields were generally lower when compared to the cross-
couplings, especially in the preparation of γ-substituted enamido
olefins (R′ * H) such as 1f,h. Overall the two methods for the
preparation of the R,γ-dienamide esters were complementary
and provided ready access to a variety of amino acid precursors.
1
2
The results of both methods are summarized in Table 1.
a
Method A: Pd(0)-catalyzed Suzuki cross-coupling between the
bromoenamide 3 and the boronic acid 4; method B: Horner-Emmons
olefination with phosphonate 5 and unsaturated aldehyde 6. For specific
conditions, please see the Experimental Section.
Hydrogenation Optimization Trials. The effects of ligand
substitution, solvent, and pressure were investigated for the
hydrogenation of dienamide 1d. The achievement of high
enantioselectivity is of obvious concern, but here, regioselec-
tivity is also very important. The asymmetric hydrogenation
of dienamide 1d was initially examined under a standard set of
reaction conditions (catalyst precursor ) [(COD)Rh-DuPHOS]-
OTf; S/C ) 500; 90 psi initial pressure of H2; MeOH; 25 °C;
upon the regioselectivity of the hydrogenation. In the optimum
case with Et-DuPHOS-Rh, the amount of overreduction product
i.e., the product of the reduction of both the enamide double
bond and the γ,δ double bond) dropped to <0.5%.
Other common hydrogenation catalysts derived from BINAP,
(
2
h reaction time). The i-Pr-DuPHOS-Rh catalyst gave only
moderate enantioselectivity (87.8% ee) and demonstrated little
regioselectivity by reducing both double bonds. Upon moving
to the less sterically congested Et- and Me-DuPHOS-Rh
catalysts, the enantiomeric excesses increased significantly to
14
DIPAMP, BDPP, CHIROPHOS, DIOP, and PROPHOS were
found to be inferior to Et-DuPHOS-Rh, particularly in terms
of regioselectivity, a challenge unique to these conjugated
dienamide ester substrates. The results of the hydrogenation
of 1i to 2i with different catalysts is shown in Table 2. Good
enantioselectivity (90% ee) was obtained with [(COD)Rh(R,R)-
DIPAMP]BF4 (entry 4); however, a significant amount of
>
99% ee13 and 97.9% ee, respectively. Matching the sterics
of the ligand to that of the substrate also had a profound effect
(
7) (a) Miossec, B.; Danion-Bougot, R.; Danion, D. Synthesis 1994, 1171.
b) Danion-Bougot, R.; Danion, D.; Francis, G. Tetrahedron Lett. 1990,
1, 3739.
8) Burk, M. J.; Allen, J. G.; Kiesman, W. F.; Stoffan, K. M. Tetrahedron
Lett. 1997, 38, 1309.
9) (a) Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1972, 94, 4370.
b) Lane, C. F.; Kabalka, G. W. Tetrahedron 1976, 32, 981.
(
3
(14) (a) DIOP: Kagan, H. B.; Dang, T.-P. J. Am. Chem. Soc. 1972, 94,
6429. (b) CHIRAPHOS: Fryzuk, M. D.; Bosnich, B. J. Am. Chem. Soc.
1977, 99, 6262. (c) PROPHOS: Fryzuk, M. D.; Bosnich, B. J. Am. Chem.
Soc. 1978, 100, 5491. (d) BINAP: Miyashita, A.; Yasuda, A.; Takaya, H.;
Toriumi, K.; Ito, T.; Souchi, T.; Noyori, R. J. Am. Chem. Soc. 1980, 102,
7932. (e) Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.;
Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi,
H. J. Am. Chem. Soc. 1989, 111, 9134. (f) Miyashita, A.; Takaya, H.; Souchi,
T.; Noyori, R. Tetrahedron 1984, 40, 1245. (g) DIPAMP: Knowles, W.
S.; Sabacky, M. J.; Vineyard, B. D.; Weindauff, D. J. J. Am. Chem. Soc.
1975, 97, 2567.
(
(
(
(10) For a review see Maercker, A. Org. React. 1965, 14, 335-344.
(11) Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1984, 53.
(12) Configurations of all the starting materials and products of the
coupling reactions were proven by NMR including NOE and NOESY
experiments.
(13) Minor enantiomer not detected by GC analysis.

Catalytic Hydrogenation of Enamides
J. Am. Chem. Soc., Vol. 120, No. 4, 1998 659
Table 2. Hydrogenation of 1i to 2i Using Different Catalystsa
entry
catalyst precursor
S/C
time (h)
convn (%)
% ee A (config.)
A:Bd
1
2
3
4
5
6
7
8
9
[(COD)Rh(S,S)-Et-DuPHOS]SbF
6
500:1
500:1
1000:1
500:1
1000:1
500:1
500:1
500:1
500:1
2
0.5
1
100b
99
55
43
47
15
95
11
35
99.2 (S)
97 (R)
83 (S)
90 (S)
23 (S)
10 (S)
58 (R)
59 (S)
1 (S)
200:1
25:1
5:1
2:1
11:1
7:1
15:1
2:1
6:1
[(COD)Rh(R,R)-Me-DuPHOS]OTf
RuBr (S)-BINAP
2
[(COD)Rh(R,R)-DIPAMP]BF
[(COD)Rh(R,R)-BDPP]OTf
4
2
0.5
12
0.25
1
[(COD)Rh(S,S)-CHIRAPHOS]OTf
c
RhCl(R,R)-DIOP
c
[(COD)Rh(R)-PROPHOS]OTf
[(COD)Rh(S)-BINAP]OTf
c
1
a
2
All reactions performed in MeOH with an initial pressure of 90 psi of H . Analysis by chiral capillary GC on a Chrompak Chirasil-L-Val
c
b
column followed passage through a short plug of silica. Starting material could not be detected by GC analysis. Catalyst precursor prepared in
situ. Enantiomeric purity of the overreduced material was not determined.
d
overreduced material (B) was produced after only 43% of the
starting material had been consumed. By contrast, RhCl(R,R)-
DIOP (entry 7) showed poor enantioselectivity (58%) but
allowed less overreduction. Very high enantioselectivities were
achieved with both the Me-DuPHOS-Rh and Et-DuPHOS-Rh
catalysts after short reaction times (entries 2 and 1). With Me-
DuPHOS, overreduction began to increase as the reaction
approached completion. The superior regioselectivity of Et-
DuPHOS was evidenced by negligible overreduced products
even after the standard reaction time of 2 h (used to ensure
complete conversion of starting material). Subtle forces are
uniquely balanced during catalysis by Et-DuPHOS-Rh which
combines high enantioselectivity and high regioselectivity in a
remarkably efficient and useful reaction.
Hydrogenation Results. The results of the asymmetric
catalytic hydrogenations of several enamido olefins are shown
in Table 3. Under our standard reaction conditions, we used
the Et-DuPHOS-Rh catalyst at S/C ) 500, initial pressures
ranged from 30 to 90 psi of H2, and 0.5-3 h was required to
give full conversion of the substrate. In all cases, less than 2%
overreduction was detected and the products were isolated in
better than 95% yield. Enantiomeric excesses were determined
1
6
by chiral capillary GC. All substrates were reduced racemi-
1
7
cally and intentionally overreduced for comparison to the
asymmetric reductions. In most cases separate hydrogenations
were run to prepare both enantiomeric products. Representative
gas chromatograms are shown in Figure 1.
In application of this methodology to specific substrates
several interesting observations were made. The amount of
overreduction product varied but could be minimized by careful
control of the S/C ratio, reaction time, and to a lesser degree
initial hydrogen pressure. In all cases, hydrogenation of the
enamide double bond preceded reduction of the distal double
Hydrogenation of the enamido olefins was found to be
sensitive to solvent. Low conversions of starting material were
found in the Me-DuPHOS-Rh-catalyzed hydrogenations of 1d
in the following solvents (90 psi initial pressure of H2; S/C )
5
00; 3 h reaction time): CH3CN (5.8% conversion), hexane
18
(5.6% conversion), toluene (8.1% conversion), and THF (54.2%
bond. It was found that the distal double bond of trisubstituted
γ,δ-olefins (compounds 1c,e,h) did not undergo appreciable
reduction even under forcing conditions (24 h reaction time and
90 psi initial pressure). By contrast overreduction was most
facile and difficult to control in the hydrogenation of 1l.
Hydrogenation products 2c and 2i are examples of natural
conversion). In i-PrOH, excellent conversion and stereochem-
ical induction (96.3% ee) were found; however, a significant
amount of overreduction product was formed (28.4%). High
conversions and enantioselectivities were achieved in MeOH
(98.6% conversion, 97.9% ee) and C6H6 (98.8% conversion,
19
95.6% ee), while the overreduction material amounted to <0.5%
products isolated from the seed of Aesculus californica and
from steroid metabolism by Pseudomonas testosteroni,20 re-
spectively. Either the R or S products could be prepared using
the catalyst of appropriate stereochemistry (entry 9).
for this substrate. Higher enantioselectivity combined with
better substrate solubility made MeOH the solvent of choice.
Pressure variations were studied for the hydrogenation of 1i,
but little effect on reaction times or enantioselectivities was
found. Using the Et-DuPHOS-Rh catalyst in MeOH, enantio-
selectivities varied by <0.5% ee over the pressure range 15-
(15) Burk, M. J.; Gross, M. F.; Martinez, J. P.; Straub, J. A. Unpublished
results.
(16) A 25 m Chrompack Chirasil-L-Val column was used for determina-
9
0 psi. However, for some substrates, regioselectivity could
tions of enantiomeric excesses.
(17) (a) Burk, M. J.; Harper, G. P.; Lee, J. R.; Kalberg, C. Tetrahedron
be improved at lower pressures because the rate of the
overreduction reaction decreased while the desired R,â hydro-
genation was not significantly affected.
Lett. 1994, 35, 4963. (b) Burk, M. J.; Gross, M. F. Tetrahedron Lett. 1994,
3
5, 9363.
(18) As the distal double bond of 2 was reduced, the enantiomeric excess
of the monoreduced material (2) decreased showing moderate reverse
substrate selectivity for the overreduction reaction (i.e., the major enantiomer
of 2 was preferentially reduced causing the % ee of the monoreduced
material to decrease). When the overreduction reaction was allowed to go
to completion, the % ee of the resulting fully reduced material was identical
with the initial % ee of 2.
High reaction rates and high selectivity observed in this work
is believed to be due to chelation of the metal center by the
enamide group of the substrate. Carbamates would be more
6
synthetically useful than the acetamides 1, but neither the N-Boc
nor N-CBZ derivatives of 1d or 1i were hydrogenated under
the conditions described here. Similar results were observed
with â,â-disubstituted carbamidoacrylates, where the reduced
reactivity again was rationalized by the attenuated ability of
(19) (a) Fowden, L.; Smith, A. Phytochemistry 1968, 7, 809. (b) Boyle,
J. E.; Fowden, L. Phytochemistry 1971, 10, 359. (c) Fowden, L.; Mazelis,
M. Phytochemistry 1971, 10, 2671.
(20) (a) Shaw, D. A.; Borkenhagen, L. F.; Talalay, P. Proc. Nat. Acad.
Sci. U.S.A. 1965, 54, 837. (b) Coulter, A. W.; Talalay, P. J. Biol. Chem.
1968, 243, 3238.
5
c,15
the carbamoyl group to coordinate to the rhodium center.

660 J. Am. Chem. Soc., Vol. 120, No. 4, 1998
Burk et al.
Table 3. Rh-Catalyzed Enantioselective Hydrogenation of R,â,γ,δ-Unsaturated Amino Acidsa
a
Using S/C ) 500, initial pressures from 30 to 90 psi, and 0.5-3 h reaction times in MeOH, less than 2% overreduction at 100% conversion
was observed in all cases. For specific conditions, please see the Experimental Section. b Absolute configurations were assigned by comparing the
sign of optical rotation of hydrolyzed (1 M NaOH) product with that of known N-acetyl amino acids, by analogy, and through comparison of sign
of optical rotation and chiral GC elution order with configurationally defined samples. c The (S)-enantiomer could not be detected.
Bulgecinine Synthesis. A demonstration of the use of these
γ,δ-unsaturated amino acids as chiral intermediates in synthesis
with di-tert-butyl dicarbonate in THF followed by hydrazine
in THF/MeOH (1:1) in a two-step one-pot procedure24 gave
92% of the N-Boc derivative. The tert-butyldimethylsilyl ether
was cleaved with HF-pyridine, and the methyl ester was
hydrolyzed with LiOH to give 7 in a combined 76% yield for
the three steps. Treatment of 7 with NBS effected a bromo-
lactonization onto the extant double bond, giving the desired
21
presented itself in the bulgecin natural products.
Several
syntheses of naturally occurring (-)-bulgecinine by halocy-
clization reactions have appeared,4
c-e,22
demonstrating 1,3-
stereoinduction from the amino acid R-position. We hoped to
be able to set all three stereogenic centers in this molecule based
on asymmetric hydrogenation in the first catalytic synthesis of
25
26
bromo-γ-lactone 8 and its diastereomer in a 9:1 ratio. The
key intermediate 8 thus obtained was subjected to the conditions
(
+)-bulgecinine (Scheme 2).4e,23
The required R,â,γ,δ-unsaturated amino acid was prepared
2
2
of Oppolzer to afford (+)-bulgecinine in 80% yield (NMR
by Horner-Emmons olefination in 70% yield. Catalytic
asymmetric hydrogenation using (R,R)-Et-DuPHOS-Rh at 60
psi required 2 h to give 99% of 2a in 99.3% ee. Treatment
spectroscopy).
(23) (a) Yuasa, Y.; Ando, J. Shibuya, S. J. Chem. Soc., Chem. Commun.
(
21) Imada, A.; Kintaka, K.; Nakao, M.; Shinagawa, S. J. Antibiot. 1982,
1994, 1383. (b) Yuasa, Y.; Ando, J. Shibuya, S. J. Chem. Soc., Perkin Trans.
1 1996, 793. (c) Schmeck, C.; Hegedus, L. S. J. Am. Chem. Soc. 1994,
116, 9927.
3
5, 1400.
(
22) Oppolzer, W.; Moretti, R.; Zhou, C. HelV. Chim. Acta 1994, 77,
2
363.
(24) Burk, M. J.; Allen, J. G. J. Org. Chem. 1997, 62, 7054.

Catalytic Hydrogenation of Enamides
J. Am. Chem. Soc., Vol. 120, No. 4, 1998 661
reactions. The first highly regio- and enantioselective catalytic
hydrogenations of conjugated dienamide esters using the Et-
DuPHOS-Rh catalyst were successfully demonstrated. Quan-
titative conversion of starting material was observed with short
reaction times to give γ,δ-unsaturated amino acid products with
better than 95% ee and less than 2% overreduction. The utility
of these interesting intermediates was demonstrated with the
formal asymmetric synthesis of (+)-bulgecinine.
Experimental Section
General Procedures. 1H and 13C NMR spectra were recorded on
a General Electric QE-300 spectrometer at 300.15 and 75.48 MHz,
3
respectively, in CDCl , and shifts are reported in parts per million
downfield from TMS. High-resolution mass spectra were obtained
using a JEOL JMS-SX102A spectrometer. Enantiomeric excess
determinations were made by chiral capillary GC on a Chrompack
Chirasil-L-Val column (25 m) in all cases. For TLC, system A was
3
(petroleum ether:ethyl acetate); system B was (CHCl :acetone). Un-
specified reagents were from commercial sources and used as obtained.
Substrate Preparations. Wittig Coupling (Method B) Sample
Procedure for (2Z,4Z)-Methyl 2-Acetamido-6-((tert-butyldimethyl-
silyl)oxy)hexa-2,4-dienoate (1a). To a suspension of methyl 2-acety-
lamido-2-(dimethoxyphosphinyl)acetate27 (2.1 g, 8.9 mmol) in THF (22
mL) at -78 °C was added tetramethylguanidine (1.4 mL, 11.8 mmol),
and the mixture was stirred for 15 min. (Z)-4-((tert-Butyldimethylsilyl)-
oxy)-but-2-enal28 (2.2 g, 10.7 mmol) was added, and the mixture was
stirred for 2 h at -78 °C and 2 h at room temperature. The mixture
Figure 1. Representative gas chromatograms showing the separation
of 2a and the corresponding overreduced derivative using a 25 m chiral
capillary Chirasil-L-Val column at 160 °C: (A) (R)- and (S)-2a after
2
h reduction with (S,S)-Me-DuPHOS-Rh (97% ee) showing 1.2%
overreduction product (O) at 94% conversion of starting material (SM)
a; (B) (R)- and (S)-2a after 2 h reduction with (R,R)-Et-DuPHOS-Rh
99.3% ee) showing 0.5% overreduction at full conversion of starting
1
was diluted with CHCl
saturated NaHCO , dried over MgSO
chromatography on silica gel gave 1a as a white solid (2.0 g, 70%):
3
, washed with 1 N HCl, 1 N CuSO
4
, and
(
3
4
, and concentrated in vacuo. Flash
17
material; (C) racemic overreduced product obtained with Rh-DiPFc.
1
R
f
0.64 (1:1 system A); mp 124-125 °C (needles from PE:EA); H
Scheme 2a
NMR δ 0.07 (s, 6H), 0.89 (s, 9H), 2.13 (s, 3H), 3.78 (s, 3H), 4.44 (dd,
2
6
2
H, J ) 1.6, 4.2 Hz), 5.90-6.00 (m, 1H), 5.98 (dd, 1H, J ) 11.5 Hz),
.94 (br s, 1H), 7.42 (d, 1H, J ) 11.7 Hz); 13C NMR δ 18.2, 23.6,
5.8, 52.5, 60.4, 123.3, 123.7, 127.2, 138.8, 165.4, 168.4; HRMS calcd
+
for C15
H30NO
4
Si (M + H ) m/z 316.1944, found 316.1936.
8
Suzuki Cross-Coupling (Method A) Sample Procedure for
(2Z,4E)-Methyl 2-Acetamido-6-phenylhexa-2,4-dienoate (1b). Under
an inert atmosphere, (Z)-methyl 2-acetamido-3-bromoacrylate (0.3 g,
.1 mmol), ((E)-3-phenyl-1-propenyl)boronic acid (0.5 g, 3.2 mmol),
Pd(OAc) (22 mg, 0.10 mmol), and Na CO were combined. Degassed
5% EtOH (20 mL) was added, and the sealed vessel was heated at 50
C with stirring for 4 h. The mixture was passed through plugs of
NaHCO and silica and concentrated in vacuo. Flash chromatography
on silica gel gave 1b as a white solid (0.36 g, 94%): R 0.45 (1:2 system
A); mp 118-119 °C (needles from PE:EA); H NMR δ 2.03 (s, 3H),
2
2
2
3
9
°
3
f
1
3
1
5
.39 (d, 2H, J ) 5.7 Hz), 3.65 (s, 3H), 6.00-6.30 (m, 2H), 6.95 (d,
H, J ) 9.9 Hz), 7.08-7.22 (m, 5H); 13C NMR δ 23.0, 29.3, 39.3,
2.1, 122.3, 126.1, 126.2, 128.3, 133.4, 138.6, 141.8, 165.3, 169.0;
+
HRMS calcd for C15
H18NO
3
(M + H ) m/z 260.1287, found 260.1288.
a
Reagents and conditions: (a) [((R,R)-Et-DuPHOS)-Rh]OTf, S/C
, 2 h (99.3% ee R); (b) (i) Boc O, DMAP,
, MeOH/THF (1:1) 4 h, 92%; (ii) HF-pyridine,
, 91%; (iii) 0.5 M LiOH/THF, 4:1, 91%; (c) NBS, THF, 0 °C,
min; (d) (i) TFA, CH Cl , 40 °C 3 h; (ii) 0.1 N Ba(OH) , room
(
2Z,4E)-Methyl 2-Acetamido-4-methylhexa-2,4-dienoate (1c). Ob-
tained as a white solid by method A (0.68 g, 77%): R 0.22 (1:1 system
A); mp 104.1-105.1 °C (needles from PE:EA); H NMR δ 1.75 (d,
H, J ) 6.9 Hz), 1.83 (s, 3H), 2.09 (s, 3H), 3.75 (s, 3H), 5.97 (q, 1H,
)
500/1, MeOH, 60 psi of H
THF 24 h then N
CH Cl
2
2
f
2 4
H
1
2
2
3
5
2
2
2
13
1
J ) 6.9 Hz), 7.10 (s, 1H), 7.45 (s, 1H); C NMR δ 13.0, 14.0, 22.6,
temperature, 3 h, ref 22, 80% by H NMR spectroscopy for two steps.
51.9, 120.3, 132.5, 136.7, 139.9, 166.1, 170.1; HRMS calcd for C10
H
16
-
+
NO
3
(M + H ) m/z 198.1138, found 198.1134.
Conclusion
(
2Z,4E)-Methyl 2-Acetamido-6-(tert-butyldimethylsilyl)oxy)hexa-
A variety of R,â,δ,γ-unsaturated amino acids were prepared
by Suzuki cross-coupling and Horner-Emmons olefination
2,4-dienoate (1d). Obtained as a white solid by method B (5.2 g,
8%): R 0.46 (1:1 system A); mp 124-125 °C (needles from PE:
EA); H NMR δ 0.02 (s, 6H), 0.86 (s, 9H), 2.07 (s, 3H), 3.72 (s, 3H),
.25 (m, 2H), 6.12 (dt, 1H, J ) 15.2 Hz, J ) 4.2 Hz), 6.35 (dd, 1H,
6
f
1
(
25) NOE experiments confirmed the relative stereochemistry; [R]20D )
45.8° (c ) 0.81, MeOH), mp ) 139-141 °C (CHCl3, hexanes). Oppolzer
4
-
13
J ) J ) 11.5 Hz), 7.05 (d, 1H, J ) 11.4 Hz), 7.14 (br s, 1H);
C
2
8
et al. (ref 22) found for (+)-8 [R] D ) +45.6 (c ) 0.815, MeOH), mp )
40-142 °C (CHCl3, hexanes).
NMR δ 18.2, 23.2, 25.7, 52.3, 63.0, 122.6, 123.8, 133.1, 141.8, 165.4,
1
+
1
68.6; HRMS calcd for C15
H30NO
4
Si (M + H ) m/z 316.1944, found
3
16.1943.
(26) Molecular mechanics calculations using the MacroModel 4.0 MM3
forcefield found ∆∆Gf ) 2.15 kcal/mol for the two diastereomers.
(
(
27) Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1984, 53-60.
28) Roush, W. R.; Straub, J. A.; VanNieuwenhze, M. S. J. Org. Chem.
1991, 56, 1636-1648.

662 J. Am. Chem. Soc., Vol. 120, No. 4, 1998
Burk et al.
(
2Z,4E)-Methyl 2-Acetamido-5,9-dimethyldeca-2,4,8-trienoate (1e).
(2R,4E)-Methyl 2-Acetamido-6-((tert-butyldimethylsilyl)oxy)hex-
4-eneoate (2d). General Procedure. Methyl 2-acetamido-6-((tert-
butyldimethylsilyl)oxy)hexa-2,4-dienoate (1d) (1.7 g, 5.4 mmol) and
[(COD)Rh(R,R)-Et-DuPHOS]OTf (7.0 mg) were dissolved in MeOH
Obtained as a white solid by method B (3.1 g, 77%): R 0.35 (1:1
system A); mp 91.2-92.2 °C (needles from PE:EA); H NMR δ 1.56,
.64, 1.87 (3s, 3H ea.), 2.10-2.20 (m, 4H), 2.12 (s, 3H), 3.75 (s, 3H),
.04 (br s, 1H), 5.93 (d, 1H, J ) 14.9 Hz), 6.89 (br s, 1H), 7.34 (d,
H, J ) 11.8 Hz, H-3); C NMR δ 14.1, 17.7, 23.5, 25.6, 26.4, 40.7,
2.3, 120.1, 123.4, 130.2, 132.5, 133.0, 150.6, 167.0, 168.6; HRMS
calcd for C15
(
f
1
1
5
1
5
2
(125 mL), and the vessel was charged with H (90 psi). After 2 h the
1
3
H
2
was vented and the solvent was evaporated. The crude material
was passed through a short plug of silica with acetone before the optical
purity was assayed by GC. Chromatography on silica gave pure 2d
+
H24NO
3
(M + H ) m/z 266.1756, found 266.1745.
2Z)-Methyl 2-Acetamido-4-ethylpenta-2,4-dienoate (1f). Ob-
(1.6 g, 95%): R
f
0.39 (1:2 system A); t
-45.8° (c ) 1.25, CHCl ); H NMR δ 0.02 (s, 6H),
R
7.36 min (160 °C, 30 psi,
>99% ee); [R]20
1
tained as a white solid by method B (0.15 g, 18%): R 0.67 (1:1 system
f
D
3
1
A); mp 72-73 °C (needles from PE:EA); H NMR δ 0.99 (t, 3H, 7.40
Hz), 2.04 (s, 3H), 2.20 (q, 2H, H)7.24 Hz), 3.74 (s, 3H), 5.23 (s, 2H),
.86 (s, 1H), 7.14 (br s, 1H); C NMR δ 12.7, 23.1, 27.5, 52.5, 119.6,
0.86 (s, 9H), 1.98 (s, 3H), 2.40-2.60 (m, 2H), 3.70 (s, 3H), 4.08 (dd,
2H, J ) 1.2, 4.8 Hz), 4.60-4.70 (m, 1H), 5.40-5.60 (m, 2H), 5.60
1
3
13
6
1
(br d, 1H, J ) 7.5 Hz); C NMR δ 18.3, 23.1, 25.9, 34.8, 51.8, 52.3,
24.0, 134.1, 145.0, 165.7, 169.2; HRMS calcd for C10
H16NO
3
(M +
63.2, 123.7, 134.1, 169.6, 172.3; HRMS calcd for C15
H ) m/z 316.1944, found 316.1943.
H30NO
4
Si (M +
+
+
H ) m/z 198.1130, found 198.1140.
(
2Z)-Methyl 2-Acetamido-3-(1-cyclohexeneyl)prop-2-enoate (1 h).
Obtained as a white solid (0.27 g, 17%): R 0.28 (1:2 system A); mp
45.5-146.4 °C (needles from EA:PE); H NMR δ 1.45-1.65 (m,
(2R,4E)-Methyl 2-Acetamido-5,9-dimethyldeca-4,8-dienoate (2e).
f
After 2 h reaction time at 90 psi initial pressure: R 0.42 (1:2 system
f
1
20
1
4
1
2
A); t 8.97 min (180 °C, 30 psi, >99% ee); [R] -63.3° (c ) 1.16,
R
D
1
H), 1.95-2.40 (m, 4H), 2.04 (s, 3H), 3.70 (s, 3H), 6.10-6.15 (m,
H), 6.99 (s, 1H), 7.09 (br s, 1H); C NMR δ 21.3, 22.4, 23.1, 25.9,
6.4, 52.3, 120.2, 134.1, 139.1, 139.7, 166.2, 169.9; HRMS calcd for
CHCl ); H NMR δ 1.56, 1.57 (2s, 6H), 1.65 (s, 3H), 1.90-2.20 (m,
3
1
3
2H), 1.97 (s, 3H), 2.40-2.60 (m, 2H), 3.70 (s, 3H), 4.55-4.70 (m,
1H), 4.90-5.10 (m, 2H), 6.00 (d, 1H, J ) 7.4 Hz); 13C NMR δ 16.0,
17.7, 23.1, 25.6, 26.4, 30.5, 39.7, 52.0, 52.2, 117.3, 123.8, 131.6, 134.0,
+
C
12
H
17NO
3
(M + H ) m/z 224.1287, found 224.1283.
+
(
2Z,4E)-Methyl 2-Acetamidohexa-2,4-dienoate (1i). Separated a
mixture of 4E and 4Z (97:3 4E:4Z, 2.0 g, 70%). 4E was obtained as
a white solid by method B: R
169.5, 172.6; HRMS calcd for C H NO (M + H ) m/z 268.1913,
1
5
26
3
found 268.1907.
f
0.33 (1:2 system A); mp 89.0-90.1 °C
needles from PE:EA); H NMR δ 1.75 (d, 3H, J ) 5.6 Hz), 2.02 (s,
(2R)-Methyl 2-Acetamido-4-ethylpenta-4-enoate (2f). After 2 h
1
(
reaction time at 60 psi initial pressure: R
f
0.27 (1:1 system A); t
R
5.70
); H
3
(
H), 3.69 (s, 3H), 5.95-6.30 (m, 2H), 6.92 (d, 1H, J ) 10.1 Hz), 7.59
br s, 1H); C NMR δ 18.8, 23.0, 52.1, 121.3, 126.5, 134.2, 139.2,
20
1
min (120 °C, 20 psi, 97.8% ee); [R]
D
-23.6° (c ) 1.28, CHCl
3
1
3
NMR δ 1.00 (t, 3H, J ) 7.4 Hz), 1.90-2.10 (m, 2H), 1.98 (s, 3H),
.37 (dd, 1H, J ) 8.2 Hz, J ) 14.0 Hz), 2.54 (dd, 1H, J ) 5.6 Hz, J
14.0 Hz), 3.70 (s, 3H), 4.60-4.70 (m, 1H), 4.74 (s, 1H), 4.83 (s,
+
1
65.4, 169.1; HRMS calcd for C
found 184.0978.
2Z,4E)-Methyl 2-Acetamido-5-tert-butylpenta-2,4-dienoate (1j).
Obtained as a white solid by method A (0.73 g, 72%): R 0.29 (1:1
9
H13NO
3
(M + H ) m/z 184.0974,
2
)
1
5
(
(
13
H), 5.89 (d, 1H, J ) 6.0 Hz); C NMR δ 12.1, 23.0, 28.0, 39.0,
0.6, 52.3, 112.1, 146.0, 170.0, 172.9; HRMS calcd for C10 18NO
3
f
H
1
system A); mp 101.6-102.6 °C (needles from PE:EA); H NMR δ
+
M + H ) m/z 200.1287, found 200.1291.
0
6
2
.96 (s, 9H), 2.03 (s, 3H), 3.66 (s, 3H), 6.01 (dd, 1H, J ) 3.9 Hz),
(2S)-Methyl 2-Acetamido-3-cyclohexenylpropanoate (2 h). After
.03 (s, 1H), 6.92 (dd, 1H, J ) 3.3, 3.6 Hz), 7.73 (s, 1H); 13C NMR δ
2
h reaction time at 90 psi initial pressure: R
f
0.29 (1:2 system A); t
R
2.9, 28.8, 33.8, 52.0, 120.0, 121.9, 134.7, 154.8, 165.4, 169.2; HRMS
calcd for C12
20
7
.25 min (150 °C, 20 psi, 99.5% ee); [R]
D
+29.8° (c ) 2.01, CHCl
3
);
+
H19NO
3
(M + H ) m/z 225.1365, found 225.1372.
1
H NMR δ 1.40-1.60 (m, 2H), 1.80-2.00 (m, 2H), 1.95 (s, 3H), 2.20-
(
2Z,4E)-Methyl 2-Acetamido-5-phenylpenta-2,4-dienoate (1l).
Obtained as a white solid by method A (0.31 g, 55%): R 0.35 (9:1
system B); mp 179.4-180.2 °C (needles from EA); H NMR δ 2.02
2
(
5
(
.50 (m, 2H), 3.66 (s, 3H), 4.55-4.70 (m, 1H), 5.41 (br s, 1H), 5.98
f
13
d, 1H, J ) 7.2 Hz); C NMR δ 22.0, 22.6, 22.9, 25.2, 27.7, 40.8,
1
0.6, 52.1, 125.6, 132.7, 169.7, 173.1; HRMS calcd for C12
H20NO
3
(
(
s, 3H), 3.80 (s, 3H), 6.85-6.90 (m, 2H), 7.07 (br s, 1H), 7.20-7.50
m, 6H); C NMR δ 23.7, 52.5, 122.8, 123.7, 127.3, 128.6, 130.0,
+
M + H ) m/z 226.1443, found 226.1435.
1
3
(
2R,4E)-Methyl 2-Acetamidohexa-4-enoate (2i). After 2 h reaction
time at 90 psi initial pressure: R 0.41 (1:2 system A); t 4.18 min
120 °C, 20 psi, 99.3% ee); [R]20
-57.2° (c ) 1.18, CHCl
δ 1.62 (d, 3H, J ) 6.1 Hz), 1.98 (s, 3H), 1.80-2.00 (m, 2H), 3.70 (s,
1
32.7, 136.2, 140.0, 165.4, 168.7; HRMS calcd for C14
H15NO
3
(M +
+
f
R
H ) m/z 254.1052, found 254.1045.
1
(
D
3
); H NMR
Substrate Hydrogenations. (2R,4Z)-Methyl 2-Acetamido-6-((tert-
butyldimethylsilyl)oxy)hex-4-eneoate (2a). After 2 h reaction time
at 60 psi initial pressure: R
3
(
1
1
H), 4.55-4.70 (m, 1H), 5.20-5.40 (m, 1H), 5.45-5.60 (m, 1H), 6.00
f
0.44 (9:1 system B); t
-32.6° (c ) 2.03, CHCl
R
7.36 min (160 °C,
); H NMR δ 0.02
br s, 1H); 13C NMR δ 18.0, 23.1, 35.2, 51.9, 52.3, 124.3, 130.0, 169.6,
2
0
1
3
(
0 psi, 99.3% ee); [R]
D
3
+
72.5; HRMS calcd for C
86.1135.
9
H
16NO
3
(M + H ) m/z 186.1130, found
s, 6H), 0.84 (s, 9H), 1.95 (s, 3H), 2.40-2.60 (m, 2H), 3.68 (s, 3H),
4
1
1
.12 (dd, 2H, J ) 0.7, 6.2 Hz), 4.50-4.70 (m, 1H), 5.20-5.40 (m,
13
(2S,4E)-Methyl 2-Acetamidohexa-4-enoate (ent-2i). After 2 h
reaction time at 90 psi initial pressure: t 4.97 min (120 °C, 20 psi,
99.2% ee); [R]20
+62.0° (c ) 0.99, CHCl ); please see 2i for other
characterization data.
(2S,4E)-Methyl 2-Acetamido-5-tert-butylpent-4-eneoate (2j). Af-
ter 1 h reaction time at 30 psi initial pressure: R 0.55 (1:2 system A);
tR 3.47 min (150 °C, 20 psi, 99.4% ee); [R]20 +61.4° (c ) 1.03,
H), 5.60-5.80 (m, 1H), 6.30 (br d, 1H, J ) 7.1 Hz); C NMR δ
R
8.3, 23.0, 25.8, 29.8, 51.5, 52.3, 59.0, 124.3, 133.3, 169.8, 172.2;
+
D
3
HRMS calcd for C15
H30NO
4
Si (M + H ) m/z 316.1944, found
3
16.1940.
2R,4E)-Methyl 2-Acetamido-6-phenylhex-4-eneoate (2b). After
.5 h reaction time at 30 psi initial pressure: R 0.47 (1:2 system A);
(
0
f
0
f
2
t
R
5.08 min (180 °C, 30 psi, 98.2% ee); [R]
CHCl
D
-61.1° (c ) 1.01,
D
1
CHCl3); H NMR δ 0.98 (s, 9H), 2.02 (s, 3H), 2.38-2.60 (m, 2H),
1
3
); H NMR δ 1.98 (s, 3H), 2.40-2.60 (m, 2H), 3.30-3.40 (m,
2
(
H), 3.70 (s, 3H), 4.60-4.70 (m, 1H), 5.35-5.50 (m, 1H), 5.60-5.75
3.74 (s, 3H), 4.60-4.70 (m, 1H), 5.18 (ddd, 1H, J ) 7.2, 15.6 Hz),
1
3
5.53 (d, 1H, J ) 15.6 Hz), 6.02 (br d, 1H, J ) 7.2 Hz); 13C NMR δ
m, 1H), 7.10-7.35 (m, 6H); C NMR δ 13.6, 19.7, 23.0, 24.0, 35.2,
5
1.8, 52.3, 58.8, 124.8, 126.1, 128.4, 134.0, 140.1, 169.5, 172.4; HRMS
23.1, 29.4, 33.1, 35.5, 52.0, 52.2, 105.6, 117.8, 146.7, 169.5, 172.4;
+
HRMS calcd for C H NO Si (M + H ) m/z 228.1600, found
+
calcd for C15
(
H30NO
4
Si (M + H ) m/z 262.1443, found 262.1438.
12 22
3
2
28.1592.
2S,4E)-Methyl 2-Acetamido-4-methylhex-4-eneoate (2c). After
2
h reaction time at 90 psi initial pressure: R
f
0.33 (1:1 system A); t
R
(2R,4E)-Methyl 2-Acetamido-5-phenylpenta-4-enoate (2l). After
20
4
.28 min (135 °C, 20 psi, 99.5% ee); [R]
D
+24.3° (c ) 1.02, CHCl
3
);
2 h reaction time at 90 psi initial pressure: R
f
0.30 (4:1 system B); t
R
1
20
H NMR δ 1.61 (m, 6H), 2.00 (s, 3H), 2.29 (dd, 1H, J ) 8.1, 16.5
Hz), 2.46 (dd, 1H, J ) 5.7, 13.2 Hz), 3.73 (s, 3H), 4.60 (ddd, 1H, J )
5.04 min (180 °C, 30 psi, 98.6% ee); [R]
D
-90.8° (c ) 1.11, CHCl
3
);
1
H NMR δ 1.93 (s, 3H), 2.50-2.80 (m, 2H), 3.67 (s, 3H), 4.60-4.75
(m, 1H), 5.96 (dt, 1H, J ) 7.4 Hz, J ) 15.7 Hz), 6.16 (br d, 1H, 7.5
7
.8, 13.5 Hz), 5.24 (q, 1H, J ) 6.0 Hz), 5.86 (br d, 1H, J ) 6.0 Hz);
1
3
13
C NMR δ 13.4, 15.2, 22.8, 42.2, 50.7, 52.1, 123.1, 130.5, 167.8, 173.0;
Hz), 6.37 (d, 1H, J ) 15.8 Hz), 7.10-7.30 (m, 5H); C NMR δ 23.1,
+
HRMS calcd for C15
2
H30NO
4
Si (M + H ) m/z 200.1287, found
35.7, 51.9, 52.4, 123.3, 126.1, 127.5, 128.5, 134.0, 136.6, 169.7, 172.3;
+
00.1296.
HRMS calcd for (M + H ) m/z 248.1287, found 248.1282.

Catalytic Hydrogenation of Enamides
+)-Bulgecinine Synthesis. (2R,4Z)-2-(tert-Butoxycarbamido)-6-
J. Am. Chem. Soc., Vol. 120, No. 4, 1998 663
(
(0.10 g, 91%) as an amorphous white solid: [R]22
D
-27.6° (c ) 1.08,
1
hydroxyhex-4-eneoic Acid (7). Acetamide 2a (0.30 g, 1.0 mmol),
BOC O (0.44 mL, 1.9 mmol), and DMAP (21.6 mg, 0.19 mmol) were
CHCl
3
); H NMR δ 1.42 (s, 9H), 1.50-1.70 (br m, 2H), 4.10-4.30
2
(m, 2H), 4.30-4.40 (m, 1H), 5.40-5.60 (m, 1H), 5.70-5.80 (m, 1H),
stirred in THF (2.4 mL) 20 h at rt and then held at reflux 0.5 h. The
reaction mixture was diluted with MeOH (2.4 mL) and cooled to 0 °C,
and hydrazine (0.12 mL, 3.8 mmol) was added. After 5 h the mixture
6.47 (br s, 2H); 13C NMR δ 28.3, 29.9, 53.1, 57.9, 80.4, 126.5, 132.0,
+
155.7, 175.3; HRMS calcd for C11
H20NO
5
(M + H ) m/z 246.1341,
found 246.1330.
was poured into CH
dried (MgSO ), and evaporated. Flash column chromatography on silica
gel gave the pure N-Boc derivative (0.33 g, 92%) as a colorless oil: R
2
Cl
2
, washed with 1 N HCl, CuSO
4
, and NaHCO
3
,
(2R,4R,5R) 5-Bromo-2-(tert-butoxycarbamido)-6-hydroxyhexano-
4-lactone (8). The acid 7 (76 mg, 0.33 mmol) was dissolved in THF
(3.3 mL) and treated with recrystallized NBS (65 mg, 0.36 mmol) at
4
f
22
0
-
(
.39 (9:1 system A); t
10.6° (c ) 2.21, CHCl
s, 9H), 2.40-2.60 (m, 2H), 3.67 (s, 3H), 4.12 (d, 2H, J ) 6.1 Hz),
R
7.19 min (160 °C, 30 psi, >99% ee); [R]
3
D
0 °C for 5 min. The reaction mixture was diluted with CH
with 1 N HCl and NaHCO , dried (MgSO ), and evaporated. The
residue was purified by chromatography to give pure 8 (86 mg, 80%):
2 2
Cl , washed
1
); H NMR δ 0.01 (s, 6H), 0.84 (s, 9H), 1.37
3
4
4
5
1
3
.30-4.40 (m, 1H), 5.15-5.20 (m, 1H), 5.20-5.40 (m, 1H), 5.60-
R
[R]
f
3
0.43 (1:2 system A); mp ) 139-141 °C (from CHCl :hexanes),
D
13
22
-45.8°, [R] 578 -46.9°, [R] 546 -53.2°, [R] 436 -88.8°, [R]22365
22
22
22
.70 (m, 1H); C NMR δ 18.3, 25.9, 28.2, 30.2, 52.2, 52.8, 59.0, 124.3,
+
1
33.4, 155.2, 172.4; HRMS calcd for C18
H36NO
5
Si (M + H ) m/z
-137.3° (c ) 0.81, MeOH); H NMR δ 1.42 (s, 9H), 2.20 (dd, 2H, J
) 11.5 Hz), 2.30 (br s, 1H), 2.78-2.95 (m, 1H), 3.90-4.00 (m, 2H),
4.10-4.20 (m, 1H), 4.40-4.50 (m, 1H), 4.65-4.75 (m, 1H), 5.23 (br
74.2363, found 374.2358. The N-Boc derivative (0.14 g, 0.38 mmol)
Cl (3.8 mL) was cooled to 0 °C, HF-pyridine (22 µL, 70%)
was added, and the mixture was stirred for 0.5 h. The reaction mixture
was diluted with CH Cl and washed with 1 N HCl and NaHCO , dried
MgSO ), and evaporated. Flash column chromatography on silica gel
gave the pure alcohol (91 mg, 92%) as a white solid: R 0.53 (1:2
-22.3° (c ) 1.40,
); H NMR δ 1.40 (s, 9H), 1.91 (br s, 1H), 2.40-2.70 (m, 2H),
.72 (s, 3H), 4.12 (d, 2H, J ) 6.8 Hz), 4.30-4.40 (m, 1H), 5.20-5.30
in CH
2
2
s, 1H); 13C NMR δ 28.2, 33.8, 50.8, 55.1, 63.5, 80.9, 155.4, 173.9;
+
2
2
3
HRMS calcd for C11
324.0445.
H
19BrNO
5
(M + H ) m/z 324.0447, found
(
4
f
2
2
Acknowledgment. We thank Dr. G. Dubay for obtaining
HRMS data. M.J.B. gratefully acknowledges the National
Institutes of Health (GM-51342), Eli Lilly (Grantee Award),
and Duke University for financial support.
system A); mp ) 44-45 °C (from PE:EA); [R]
CHCl
3
D
1
3
1
3
(
3
m, 1H), 5.40-5.50 (m, 1H), 5.70-5.80 (m, 1H); C NMR δ 28.2,
0.3, 52.4, 53.0, 58.0, 126.1, 132.6, 155.3, 172.5; HRMS calcd for
+
C
12
H22NO
5
(M + H ) m/z 260.1498, found 260.1501. The alcohol
Supporting Information Available: Representative NMR
spectra and gas chromatograms for compounds 1 and 2 including
the formal synthesis of (+)-bulgecinine (29 pages). See any
current masthead page for ordering and Internet access
instructions.
methyl ester (0.12 g, 0.48 mmol) in THF (4.8 mL) was stirred at 0 °C
with 0.5 M LiOH (1.2 mL) 0.75 h. The mixture was diluted with CH
Cl and acidified (48 µL of 12 M HCl), and the aqueous layer was
saturated with NaCl. After the mixture was stirred for 1 h, the organic
layer was separated off, washed with 1 N HCl, dried (MgSO ), and
evaporated. The residue was washed with (9:1 PE:EA) to give pure 7
2
-
2
4
JA9731074