Diastereoselective Baylis-Hillman reactions: The design and synthesis of a novel camphor-Based chiral auxiliary

Article abstract of DOI:10.1021/ol990315n

Formula presented Reaction of chiral acryloylhydrazide 5 derived from novel auxiliary 4 with aldehydes in the presence of DABCO affords practical levels (up to 98percent de) of β-hydroxy-α-methylene carbonyl derivatives, and high optical purity of both di

Full text of DOI:10.1021/ol990315n

ORGANIC
LETTERS
2000
Vol. 2, No. 6
729-731
Diastereoselective Baylis−Hillman
Reactions: The Design and Synthesis
of a Novel Camphor-Based Chiral
Auxiliary
Kung-Shuo Yang and Kwunmin Chen*
Department of Chemistry, National Taiwan Normal UniVersity, 88 Sec. 4,
TingChow Road, Taipei, Taiwan 116, ROC
kchen@scc.ntnu.edu.tw
Received October 5, 1999 (Revised Manuscript Received January 3, 2000)
ABSTRACT
Reaction of chiral acryloylhydrazide 5 derived from novel auxiliary 4 with aldehydes in the presence of DABCO affords practical levels (up to
98% de) of â-hydroxy-r-methylene carbonyl derivatives, and high optical purity of both diastereomers of 6a−d and 7a−d can be obtained by
changing the solvent.
The synthesis of both enantiomers of a chiral compound is
a very important task in asymmetric synthesis. To attain this
goal, traditional methods require the use of either antipode
of chiral material to obtain stereoisomers with opposite
configurations.1 From a practical synthetic point of view,
the preparation of both stereoisomers with excellent optical
purity derived from the same chiral source is an attractive
tool.2 The Oppolzer camphor sultam is among the most
promising chiral auxiliaries presently available in asymmetric
reactions.3 The search for structurally related auxiliaries for
asymmetric synthesis continues, especially functional group
modifications at the C10 position.4 This fact and the great
utility of the chiral sultam and related auxiliaries in stereo-
selective synthesis provided the motivation to develop a novel
variant from which both diastereomers could be prepared
using the same camphor scaffold. To the best of our
knowledge, only a few examples of preparing both individual
stereoisomers with high optical purity from a single enan-
tiomer of chiral source have been reported.2,4a,b
The coupling of an R,â-unsaturated carbonyl/nitrile with
an aldehyde (Baylis-Hillman reaction) provides useful
(3) (a) Liu, J.; Eddings, A.; Wallace, R. H. Tetrahedron Lett. 1997, 38,
6795. (b) Wallace, R. H.; Liu, J.; Zong, K. K.; Eddings, A. Tetrahedron
Lett. 1997, 38, 6791. (c) Kim, B. H.; Lee, J. Y.; Kim, Y.; Whang, D.;
Tetrahedron: Asymmetry 1991, 2, 27. (d) Kim, B. H.; Lee, J. Y.
Tetrahedron: Asymmetry 1991, 2, 1359. (e) Kim, B. H.; Curran, D. P.
Tetrahedron 1993, 49, 293. (f) Mish, M. R.; Guerra, F. M.; Carreira, E. M.
J. Am. Chem. Soc. 1997, 119, 8379. (g) Oppolzer, W. Angew. Chem., Int.
Ed. Engl. 1984, 23, 876.
(4) For the syntheses of novel camphor-derived chiral auxiliaries and
their synthetic applications, see: (a) Chen, C.-J.; Chu, Y.-Y.; Liao, Y.-Y.;
Tsai, Z.-H.; Wang, C.-C.; Chen, K. Tetrahedron Lett. 1999, 40, 1141. (b)
Chu, Y.-Y.; Yu, C.-S.; Chen, C.-J.; Yang, K.-S.; Lain, J.-C.; Lin, C.-H.;
Chen, K. J. Org. Chem. 1999, 64, 6993. (c) Yan, T.-H.; Hung, A.-W.; Lee,
H.-C.; Chang, C.-S.; Liu, W.-H. J. Org. Chem. 1995, 60, 3301. (d) Yan,
T.-H.; Chu, V.-V.; Lin, T.-C.; Tseng, W.-H.; Cheng, T.-W. Tetrahedron
Lett. 1991, 32, 5563. (e) Kaye, P. T.; Molema, W. E. J. Chem. Soc., Chem.
Commun. 1998, 2479. (f) Ahn, K. H.; Lee, S. Lim, A. J. Org. Chem. 1992,
57, 5065.
(1) (a) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345. (b)
Oppolzer, W.; Kingma, A. J.; Pillai, S. K. Tetrahedron Lett. 1991, 32, 4893.
(2) (a) Kobayashi, S.; Horibe, M. Tetrahedron 1996, 52, 7277. (b)
Alvarez-Ibarra, C.; Csa´ky¨, A. G.; Maroto, R.; Quiroga, M. L. J. Org. Chem.
1995, 60, 7934. (c) Meyer, L.; Poirier, J.-M.; Duhamel, P.; Duhamel, L. J.
Org. Chem. 1998, 63, 8094. (d) Solladie, G.; Greck, C.; Demailly, G.;
Solladie-Cavallo, A. Tetrahedron Lett. 1982, 23, 5047. (e) Kobayashi, S.;
Hayashi, T. J. Org. Chem. 1995, 60, 1098. (f) Kobayashi, S.; Horibe, M.;
Saito, Y. Tetrahedron 1994, 50, 9629. (g) Kobayashi, S.; Horibe, M. J.
Am. Chem. Soc. 1994, 116, 9805. (h) Sibi, M.; Shay, J. J.; Liu, M.; Jasperse,
C. P. J. Am. Chem. Soc. 1998, 120, 6615. (i) Kobayashi, S.; Kusakabe, K.;
Komiyama, S.; Ishitani, H. J. Org. Chem. 1999, 64, 4220.
10.1021/ol990315n CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/19/2000

intermediates possessing a contiguous assembly of varied
functionalities.5 The reaction is mediated by a tertiary amine,
and 1,4-diazabicyclo[2.2.2]octane (DABCO) is the most
common catalyst employed. The resulting â-hydroxy-R-
methylene carbonyl derivatives are versatile synthetic inter-
mediates in organic synthesis.6 The asymmetric version of
the Baylis-Hillman reaction has attracted much attention
in recent years.7 Among these methods, the reaction of chiral
Michael acceptors with an aldehyde is a conventional
strategy.8 Only a few examples, however, provide practical
levels of â-hydroxy-R-methylene carbonyl derivatives. Leahy
and co-workers have reported the use of camphor sultam in
the Baylis-Hillman reaction.8a Excellent optical purity of
lactones were obtained when camphor sultam was treated
with various aldehydes in the presence of DABCO (eq 1).
with acryloyl chloride provided acryloylhydrazide 5 in 96%
yield. The overall yield is 85% in four steps from the
corresponding known starting material. The structure of 5
was unambiguously characterized by spectroscopic analyses
and HRMS and further confirmed by single-crystal X-ray
analysis.
Treatment of compound 5 with DABCO (0.1 equiv) and
acetaldehyde in neat conditions at room temperature for 8 h
afforded the inseparable isomeric products 6a and 7a (75/
25) in a total yield of 92% (Table 1, entry 1). The
diastereomeric ratio was determined by HPLC analysis. An
even more disappointingly low ratio of 6a/7a (58/42) was
observed when the reaction was carried out in THF at room
temperature (entry 2). The diastereoselectivity was signifi-
cantly improved when an aprotic solvent (DMSO) was used
(entry 3). The reaction proceeded smoothly with a ratio of
97/3 in favor the formation of 6a. The structure of 6a was
characterized by 1H and 13C NMR and HRMS analyses, and
the absolute stereochemistry was established by single-crystal
X-ray analysis. High diastereoselectivity was generally
observed when different aldehydes were used (propionalde-
hyde, 3-phenylpropionaldehyde, 3-methylbutyraldehyde, and
benzaldehyde) (entries 4-7). Interestingly, the sense of
stereoselectivity was reversed when the reaction was carried
out in a mixed solvent system. Thus, treatment of 5 with
acetaldehyde in THF/H2O (5/1) at room temperature for 96
h affords 6a/7a in a ratio of 3/97 (entry 8). The influence of
solvent polarity that causes the complete reversal of dia-
stereoselectivity deserves special attention (compare entries
3, 8; 4, 9; 5, 10; and 6, 11). This creates a surprising scenario
where apparently the transition state conformation is highly
solvent-dependent. The reaction of 5 with benzaldehyde in
THF/H2O for 3 weeks resulted in a trace amount of products
(entry 12). On the other hand, one of the unidentified product
was isolated when R-branched aldehydes were used (entries
13 and 14). The structure was tentatively assigned to be a
It is noteworthy that the sultam auxiliary is automatically
removed with the second equivalent of aldehyde.
In this Letter we wish to report the synthesis and use of 4
as a highly efficient chiral auxiliary for the asymmetric
induction of the Baylis-Hillman reaction. Instead of provid-
ing the lactone products, high optical purities of â-hydroxy-
R-methylene carbonyl derivatives can be obtained when 5
is treated with aldehyde. Further, either diastereomer of 6a-d
and 7a-d can be prepared in high purity by the appropriate
choice of reaction conditions.
Treatment of (+)-ketopinic acid9 1 with phenylhydrazine
under acidic conditions provided 2 in 95% yield (Scheme
1). The cyclization proceeded smoothly when 2 was treated
1
dimerized compound of 5 by H NMR analysis.10
Scheme 1
(5) For reviews of the Baylis-Hillman reaction, see: (a) Ciganek, E.
Org. React. 1997, 51, 201. (b) Basavaiah, D.; Dharma Rao, P.; Hyma, R.
S. Tetrahedon 1996, 52, 8001. (c) Drewes, S. E.; Roos, G. H. P. Tetrahedron
1988, 44, 4653.
(6) (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93,
1307. (b) Atkinson, R. S.; Fawcett, J.; Russell, D. R.; Williams, P. J. J.
Chem. Soc., Chem. Commun. 1994, 2031. (c) Basavaiah, D.; Bhavani, A.
K. D.; Pandiaraju, S.; Sarma, P. K. S. Synlett 1995, 243. (d) Annunziata,
R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Raimondi, L. J. Org. Chem.
1995, 60, 4697. (e) Brzezinski, L. J.; Rafel, S.; Leahy, J. W. Tetrahedron
1997, 53, 16423.
(7) (a) Oishi, T.; Oguri, H.; Hirama, M. Tetrahedron: Asymmetry 1995,
6, 1241. (b) Hayase, T.; Shibata, T.; Soai, K.; Wakatsuki, Y. J. Chem. Soc.,
Chem. Commun. 1998, 1271. (c) Barrett, A. G. M.; Cook, A. S.; Kamimura,
A. J. Chem. Soc., Chem. Commun. 1998, 2533.
(8) (a) Brzezinski, L. J.; Rafel, S.; Leahy, J. W. J. Am. Chem. Soc. 1997,
119, 4317. (b) Drewes, S. E.; Emslie, N. D.; Khan, A. A. Synth. Commun.
1993, 23, 1215. (c) Basavaiah, D.; Gowriswari, V. V. L.; Sarma, P. K. S.;
Dharma Rao, P. Tetrahedron Lett. 1990, 31, 1621. (d) Gilbert, A.; Heritage,
T. W.; Isaacs, N. S. Tetrahedron: Asymmetry 1991, 2, 969.
(9) Bartlett, P. D.; Knox, L. H. Organic Syntheses; Wiley: New York,
1973; Collect. Vol. V, p 689.
(10) (a) Basavaiah, D.; Growriswari, V. V. L.; Bharathi, T. K. Tetra-
hedron Lett. 1987, 28, 4591. (b) Basavaiah, D.; Gowriswari, V. V. L.;
Dharma Rao, P.; Bharathi, T. K. J. Chem. Res., Synop. 1995, 267. (c)
Drewes, S. E.; Emslie, N. D.; Karodia, N. Synth. Commun. 1990, 20, 1915.
(d) Amri, H.; Rambaud, M. Villieras, J. Tetrahedron Lett. 1989, 30, 7381.
with SOCl2 in EtOAc in the presence of Et3N. The C-N
double bond in 3 was reduced with NaBH4 to give 4 as the
sole product in excellent yield. Acylation of the auxiliary 4
730
Org. Lett., Vol. 2, No. 6, 2000

Table 1. Asymmetric Baylis-Hillman Reaction of Acryloylhydrazide 5 with Aldehydesa
entry
RCHO (R ))
solvent
neat
THF
DMSO
DMSO
DMSO
DMSO
DMSO
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
DMSO
time (days)
6/7
ratiob
yield (%)c
confignd
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Me
Me
Me
Et
PhCH2CH2
Me2CHCH2
Ph
Me
Et
PhCH2CH2
Me2CHCH2
Ph
iPrg
tBug
1/3
1/2
2
4
4
2
7
4
3
3
3
21
4
1/3
6a /7a
6a /7a
6a /7a
6b/7b
6c/7c
6d /7d
6e/7e
6a /7a
6b/7b
6c/7c
6d /7d
6e/7e
75/25
58/42
97/3
99/1
99/1
97/3
99/1
3/97
1/99
1/99
1/99
92
82
88
85
80
75
80
73
85
68
81
0
S
S
Se
Se
Se
Sf
Se
R
R
R
Re
DMSO
a All reactions were carried out at 25 °C at atmospheric pressure. b Ratios determined by HPLC analysis on a J. T. Baker standard silica gel column (4.6
× 250 mm, 5 µm; hexane/iPrOH ) 95/5, 0.6 mL/min). Retention time: 6a (30.4 min), 7a (24.2 min); 6b (20.5 min), 7b (15.9 min); 6c (17.4 min), 7c (13.1
min); 6d (15.2 min), 7d (11.3 min); 6e (14.8 min). c Yields of isolated products after flash column chromatography. d Major diastereomer of the newly
generated stereogenic center. e The absolute stereochemistry was established by X-ray crystallography. f The absolute stereochemistry was established by
analogy. g One of the unidentified products was isolated.10
The exact mechanistic explanation of this study remains
unclear at the present time. The stabilization, however, of
the zwitterion intermediate by intermolecular hydrogen
bonding with the solvent molecules and/or the disruption of
the intramolecular ionic bond by DMSO might play a crucial
role in determining the stereochemical outcome. The avoid-
ance of steric interaction between the R group of the aldehyde
and the camphor skeleton might also be important. More
information is needed before the puzzle can be answered.
In this study, either diastereomer of the â-hydroxy-R-
methylene carbonyl deriVatiVes with high optical purity can
be obtained by the appropriate choice of reaction conditions.
It is noteworthy that both the degree of diastereoselectivity
and the reaction rate appear to be concentration dependent.
In summary, an efficient route for the preparation of chiral
auxiliary 4 has been developed, and compound 5 has been
successfully used as a novel chiral Michael acceptor for the
Baylis-Hillman reaction to achieve high stereoselection. Our
procedure represents a simple and effective alternative for
the highly diastereoselective synthesis of â-hydroxy-R-
methylene carbonyl derivatives. MoreoVer, both diastereo-
mers of 6a-d and 7a-d with high optical purity can be
prepared from the same chiral auxiliary by means of the
proper choice of reaction conditions. Further investigations
on an enantiomeric version of the Baylis-Hillman reaction
will be reported in due course.
Acknowledgment. Financial support by the National
Science Council of the Republic of China and the collection
and processing of the X-ray data for 5, 6a-c, and 6e by
Professor C.-H. Ueng (National Taiwan Normal Univeresity)
and the Taipei Instrumentation Center, College of Science
(National Taiwan University), are gratefully acknowledged.
Supporting Information Available: 1H and 13C NMR
spectra for compounds 2, 3, 4, 5, 6a-e, and 7a-d and X-ray
crystallographic data (table of atomic coordinates, hydrogen
coordinates, and bond lengths and angles and ORTEP
diagrams) for structures 5, 6a-c, and 6e. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL990315N
Org. Lett., Vol. 2, No. 6, 2000
731