Concise asymmetric synthesis of (5R)-6-hydroxy-3,8-dioxabicyclo[3.2.1] octane derivatives

Article abstract of DOI:10.1021/ol049008u

(Chemical Equation Presented) A concise method to asymmetrically synthesize 6-hydroxy-3,8-dioxabicyclo[3.2.1]octane (HDBO) derivatives was devised.

Full text of DOI:10.1021/ol049008u

ORGANIC
LETTERS
2004
Vol. 6, No. 18
3059-3061
Concise Asymmetric Synthesis of
(5R)-6-Hydroxy-3,8-dioxabicyclo[3.2.1]octane
Derivatives
Chong-Feng Pan, Zu-Hui Zhang, Gao-Jun Sun, and Zhi-Yong Wang*
Department of Chemistry, UniVersity of Science and Technology of China, Hefei,
Anhui, 230026, P. R. China
zwang3@ustc.edu.cn
Received May 28, 2004
ABSTRACT
A concise method to asymmetrically synthesize 6-hydroxy-3,8-dioxabicyclo[3.2.1]octane (HDBO) derivatives was devised.
3,8-Dioxabicyclo[3.2.1]octane (DBO) exists in natural prod-
ucts and their analogues, notably, in the bicyclic analogues
of zoapatanol. Zoapatanol, isolated from the leaves of the
zoapatle plant (Montanoa tomentosa), has attracted much
attention for its antifertility activity and structure features
(Figure 1, a).1 Several of its bicyclic analogues have been
synthesized, and they possess an even higher antifertility
activity (one example is shown in Figure 1, b).2 6-Hydroxy-
3,8-dioxabicyclo[3.2.1]octane (HDBO) also exists in bio-
active compounds such as some conformationally restricted
nucleoside analogues.3
(IPG). The corresponding product was obtained with a
relatively high total yield and a high enatiomeric excess (ee).
The retrosynthetic analysis is shown in Scheme 1. The
C(2)-O(3) bond in the target molecule i is disconnected to
give the intermediate ii. ii is a typical product of iodo-
cyclization reaction5 and can be accessed from iii. Retrosyn-
thetic ketal formation of iii leads to iv. The C(1)-C(2) bond
in iv is disconnected, which gives allylic substrate v and IPG
vi. The retrosynthetic analysis makes it clear that, in the
actual synthetic procedure, iodocyclization of iii not only
Traditional synthetic methods took at least seven steps to
construct DBO or HDBO,3,4 which usually had a low yield.
In this paper, we propose a new, concise method to
asymmetrically synthesize HDBO derivatives in only four
steps, starting from (R)-2,3-O-isopropylideneglyceraldehydes
(1) Levine, S. D.; Adams, R. E.; Chen, R.; Cotter, M. L.; Hirsch, A. F.;
Kane, V. V.; Kanojia, R. M.; Shaw, C.; Wachter, M. P.; Chin, E.;
Huettemann, R.; Ostrowski, P.; Mateos, J. L.; Noriega, L.; Guzman, A.;
Mijarez, A.; Tovar, L. J. Am. Chem. Soc. 1979, 101, 3404.
(2) (a) Kanojia, R. M.; Chin, E.; Smith, C.; Chen, R.; Rowand, D.;
Levine, S. D.; Wachter, M. P.; Adams, R. E.; Hahn, D. J. Med. Chem.
1985, 28, 796. (b) Walba, D. M.; Stoudt, G. S. J. Org. Chem. 1983, 48,
5404. (c) Takayanagi, H.; Shirasaka, T.; Morita, Y. Synthesis 1991, 722.
(3) Kaemo, L.; Wengel, J. J. Org. Chem. 2001, 66, 5498.
(4) (a) Chen, R.; Hajos, Z. G. J. Org. Chem. 1984, 49, 4743. (b) Wachter,
M. P.: Hajos, Z. G.; Adams, R. E.; Werblood, H. M. J. Org. Chem. 1985,
50, 2216.
Figure 1. Zoapatanol (a) and one of its bicyclic analogues (b).
10.1021/ol049008u CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/11/2004

Scheme 1. Retrosynthetic Analysis
Table 1.
entry
allylic substrate
isolated yield(%)
anti:syna
1
2
3
4
1a
1b
1c
1d
87
84
78
81
75:25
83:17
93:7
90:10
1
a Ratio was estimated by H NMR experiment.
forms the tetrahydrofuran ring, but also prepares it for the
subsequent intramolecular etherification. The synthetic route
is shown in Scheme 2.
the allylation of IPG in water, from which we hoped to obtain
the desired anti isomer. It was reported that an anti isomer
dominated in the In-THF-H2O system.7 However, for our
purpose the use of relatively expensive indium made the
system undesirable. Therefore, we tried different systems.
In our experiments, it was found that freshly prepared chiral
IPG favored high ee of products because the enolization of
carbonyl group of IPG resulted in slow racemization. The
reaction was thus required to be completed as quickly as
possible. After many trials, the Zn-SnCl2-H2O system was
identified. Here the use of the water solvent avoided the
tedious purification of the starting materials, such as desic-
cation and removal of air, and this allowed us to immediately
use the freshly prepared IPG for the allylation. The allylation
reaction can be completed within 30 min, giving us the anti
isomer of 2 in a moderate yield, as shown in Table 1. The
enhancement of the steric hindrance of R1 led to the increase
of the diastereoselectivity, with a slight decrease of the yield.
The existence of the electron-withdrawing group slightly
increased the yield (entries 3 and 4, Table 1).
Scheme 2. Synthesis of
6-Hydroxy-3,8-dioxabicyclo[3.2.1]octane Derivatives
Hydrolysis of the ketal 2 in 1 M HCl proceeded smoothly
at room temperature to give rise to 3.
Two isomers were generated from the iodocyclization
reaction (Scheme 3), and the cis isomer was the predominant
product. Following the procedure described in the literature,5
initially, we got the desired product in a high diastereo-
selectivity but with a low yield. Higher temperature enhanced
the total yield of these two isomers but decreased the
diastereoselectivity. Therefore, we had to resolve the conflict
between yield and diastereoselectivity. Many attempts proved
that low temperature favored the diastereoselectivity. After
optimization, we prolonged the reaction time to 24 h and
gradually increased the amount of iodine to a large excess
at 0 °C, resulting in a complete disappearance of the starting
material without any sacrifice of the selectivity.
The synthesis began with the allylation of IPG (Table 1).
Stereoselective synthesis of syn or anti isomers by using
appropriate chiral allylborane reagents and titanium reagent
is known.6 Pursuing an economical and more convenient
method, we decided to carry out the first step by employing
The intramolecular etherification of 4 was first performed
by using NaH in HMPA-THF.4b The low yield (<28%)
(6) (a) Roush, W. R.; Grover, P. T. J. Org. Chem. 1995, 60, 3806. (b)
Roush, W. R.; Hoong, L. K.; Palmer, M. A. J.; Straub, J. A.; Palkowitz, A.
D. J. Org. Chem. 1990, 55, 4117. (c) Cossy, J.; Willis, C.; Bellosta, V.;
BouzBouz, S. J. Org. Chem. 2002, 67, 1982.
(5) Rychnovsky, S. D.; Bartlett, P. A. J. Am. Chem. Soc. 1981, 103,
3963.
(7) Paquette, L. A.; Mitzel, T. M. J. Am. Chem. Soc. 1996, 118, 1931.
3060
Org. Lett., Vol. 6, No. 18, 2004

six-membered ring transition state may have been involved
in the formation of 2e, as shown in Scheme 4.7 First of all,
crotyltin or crotylzinc chelates to the two oxygen atoms from
the carbonyl group and the neighboring dioxolane group,
respectively. Following Cram’s rule, the crotyl group trans-
fers to the carbonyl carbon from the less hindered π-surface
through the six-membered ring transition state, which results
in the (R)-configuration of C(1). On the other hand, the
methyl group from crotyl bromide and the bulky dioxolane
group adopt a trans arrangement in this six-membered ring
transition state to further reduce the steric hindrance, which
results in the (R)-configuration of C(2). As a result, the
γ-adduct 2e is formed as the main product. Afterward, 2e
was smoothly converted to 5e by the same procedure as
described above.8
Scheme 3. Iodocyclization
called for further improvement. Sodium hydride, which is a
strong base, failed to improve the etherification, which
suggested that the C-I bond needed to be activated. To
validate this idea, 4c and saturated AgNO3 solution were
mixed together. A black precipitate was observed, and 5c
was isolated in 55% yield, accompanying some unidentified
byproducts. After optimizing the reaction conditions, the
AgNO3-K2CO3-methanol system was identified for the
etherification and 4c was converted to 5c with a 91% yield.
Afterward, 5a′, 5b, and 5d were prepared smoothly by using
this concise method. The structure of 5 was definitively
characterized by 1H NMR, 13C NMR, HRMS, H-H NOESY,
and H-H COSY, which unambiguously assigned an anti
configuration to 2.8
The overall yield of 5a-e and the corresponding ee are
summarized in Table 2. It was found that aromatic substi-
Table 2.
Scheme 4
tutents in allylic substrates favored both the iodocyclization
and the intramolecular etherification (entries 3 and 4, Table
2).
In summary, we devised a short and efficient synthetic
route for HDBO derivatives by use of chiral aldehyde
synthons, (R)-2,3-O-isopropylideneglyceraldehydes. High
diastereoselectivity of the allylation reaction was reached
when the allyl bromide was substituted with an aryl group.
Further improvement and application of this method to the
total synthesis of natural products is underway in our lab.
To extend the scope of the reaction substrate, crotyl
bromide also was used to construct this bicycle (Scheme 4).
In the crotylation reaction, we attempted to obtain six
isomers, two from R-addition and four from γ-addition. In
our experiment, at least four spots were observed in TLC,
of which 2e was the main product obtained in 36% yield. A
Acknowledgment. The authors are grateful to National
Nature Science Foundation of China (No. 50073021) and
National Nature Science Foundation of Anhui Province (No.
01046301) for their support. We are grateful for the referees’
excellent suggestions.
Supporting Information Available: Experimental pro-
cedures and product characterization data for compounds
2a-e, 3a′-e, 4a′-e, 5a′-e. This material is available free
of charge via the Internet at http://pubs.acs.org.
(8) It was difficult to distinguish the two isomers of 2 only from their
1H NMR spectra. Both isomers gave overlapped multiplets between δ 3.5-
4.3. Here we solved this problem by determining the configuration of 5
first. It is easy to ascertain the configuration of 5 by NOESY. Then, the
configuration of 2 was determined easily according to the configuration of
5.
OL049008U
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