Asymmetric synthesis of octahydrobenzofuran core structure with three contiguous stereogenic centers and development of the absolute configurations

Article abstract of DOI:10.1080/00397911.2013.791698

Cyclization of enantiopure (S/R)-1 with halogen-reagent-constructed enantiopure octahydrobenzofuran core structure with contiguous three stereogenic centers of both enantiomers (SRR and RSS). The absolute configurations of all compounds have been establis

Full text of DOI:10.1080/00397911.2013.791698

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Asymmetric Synthesis of
Octahydrobenzofuran Core Structure
with Three Contiguous Stereogenic
Centers and Development of the
Absolute Configurations
a
a
a
a
Muhammad Sohail , Yao-Feng Wang , Shaoxiang Wu , Wei Zeng
a
&
a
Fu-Xue Chen
Department of Applied Chemistry , School of Chemical Engineering
and the Environment, Beijing Institute of Technology , Beijing ,
China
Accepted author version posted online: 15 Aug 2013.Published
online: 11 Oct 2013.
To cite this article: Muhammad Sohail , Yao-Feng Wang , Shaoxiang Wu , Wei Zeng & Fu-Xue
Chen (2014) Asymmetric Synthesis of Octahydrobenzofuran Core Structure with Three Contiguous
Stereogenic Centers and Development of the Absolute Configurations, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:1, 115-120, DOI:
10.1080/00397911.2013.791698
To link to this article: http://dx.doi.org/10.1080/00397911.2013.791698
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1
Synthetic Communications , 44: 115–120, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.791698
ASYMMETRIC SYNTHESIS OF
OCTAHYDROBENZOFURAN CORE STRUCTURE
WITH THREE CONTIGUOUS STEREOGENIC
CENTERS AND DEVELOPMENT OF THE
ABSOLUTE CONFIGURATIONS
Muhammad Sohail, Yao-Feng Wang, Shaoxiang Wu,
Wei Zeng, and Fu-Xue Chen
Department of Applied Chemistry, School of Chemical Engineering and the
Environment, Beijing Institute of Technology, Beijing, China
GRAPHICAL ABSTRACT
Abstract Cyclization of enantiopure (S/R)-1 with halogen-reagent-constructed enantiopure
octahydrobenzofuran core structure with contiguous three stereogenic centers of both
enantiomers (SRR and RSS). The absolute configurations of all compounds have been
established from x-ray analysis of the single crystal of (3aS,7aR,7R)-3. The chiral
initiation in diastereoselective mode of 5-exo ring closure across C=C bond of pendant
cyclohexene moiety has been proposed.
[Supplementary materials are available for this article. Go to the publisher’s online
1
edition of Synthetic Communications for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Asymmetric synthesis; heterocyclic; octahydrobenzofuran; stereoselectivity
INTRODUCTION
Development of new and stereospecific organic reactions is a goal for synthetic
[
1]
chemists. Tetrahydrofuran derivatives are well known versatile precursors for the
construction of a variety of natural products and therapeutic drugs. Hence, the
synthesis of these compounds and their analogs has received increasing research
[
2]
[3]
interests. Previously, octahydrobenzofurans, the core structure of many drugs
Received February 22, 2013.
Address correspondence to Fu-Xue Chen, Department of Applied Chemistry, School of Chemical
Engineering and the Environment, Beijing Institute of Technology, 5 South Zhongguancun Street,
Haidian District, Beijing 100081, China. E-mail: fuxue.chen@bit.edu.cn
1
15

116
M. SOHAIL ET AL.
[4]
and natural products, were synthesized (with single to multistep) by free radical
[8]
[
5]
[6]
reactions, reduction, tandem conjugate addition, base-catalyzed cyclization,
[7]
[
9]
[10]
and acid and photochemical rearrangement as the key steps. However, all these
compounds were obtained in racemic mixture. Although preparative and mechan-
istic detail of 5-exo ring closure across C=C bond of cyclohexene with exclusive for-
[
11]
mation of anti-addition product has been reported recently,
the asymmetric
synthesis still remains challenging. Herein, we report our construction of the core
structure octahydrobenzofuran with excellent diastereo- and enantioselectivity from
discrete cycloalkenylalcohol under mild reaction conditions.
RESULTS AND DISCUSSION
0
We have targeted the chiral center at the C-1 position of cyclic c-alkenyl
alcohol 1. In this regard, the starting material 1 was synthesized and resoluted by
[12]
spontaneous resolution.
Each enantiomer was obtained in crystal with optical
purity >99% ee from n-hexane. To evaluate the mode of chiral induction in this type
of cyclization, initially, discrete (S)-(ꢀ)-1 was treated with a catalytic amount of
[13]
TfOH in CH Cl , resulting in the exclusive formation of 5-exo-ring closure pro-
2
2
duct (3aS,7aS)-(ꢀ)-2 (Table 1, entry 1). As expected, the extremely opposite enantio-
mer (3aR,7aR)-(þ)-2 was produced with the opposite starting material (R)-(þ)-1
0
(
1
Table 1, entry 2). The chiral center at C-1 is the origin of this selectivity through
,2-chiral induction. Keeping in view this observation, we extended our study and
0
sought to gain additional information regarding the selectivity at C-3 . Possible
approaches for the facile formation of C-X bond were examined which delivered
the desired stereoutcome in high efficiency.
a
Table 1. Chiral induction in 5-exo ring closure across C=C bond of pendant c-hexene
b
Entry
Substrate
Halogen reagent
Product
Yield (%)
ee (%)
c
1
(S)-(ꢀ)-1
(R)-(þ)-1
(S)-(ꢀ)-1
(R)-(þ)-1
(R)-(þ)-1
(R)-(þ)-1
(R)-(þ)-1
—
—
(3aS,7aS)-(–)-2
(3aR,7aR)-(þ)-2
(3aS,7aR,7R)-(–)-3
(3aR,7aS,7S)-(þ)-3
(3aR,7aS,7S)-(þ)-4
5
100
100
99
>99.9
>99.9
>99.9
>99.9
>99.9
—
c
2
3
4
5
6
NIS
NIS
NBS
NCS
6
99
84
NR
70%
d
7
(3aR,7aS,7S)-(þ)-5
>99.9
a
ꢁ
Reaction conditions: 1 (0.05 mmol), halogen reagent (0.06 mmol, 1.2 equiv), ꢀ78 C,
2 2
CH Cl (0.5 mL), 3 h, argon atmosphere.
b
Determined by chiral HPLC on AS-H and OD-H.
TfOH (0.005 mmol, 10 mol%), reflux.
c
d
6 is 1,3-dichloro-5,5-dimethylhydantoin.
Notes. NIS, N-iodosuccinimide; NBS, N-bromosuccinimide; NCS, N-chlorosuccinimide.

ASYMMETRIC SYNTHESIS OF OCTAHYDROBENZOFURAN
117
To solve the desired ambiguity, N-iodosuccinimide (NIS) was chosen as the
model halogen reagent, which worked effectively in the absence of any catalyst.
Good yield of haloetherification product (3aS,7aR,7R)-3 was obtained in CH Cl
2
2
ꢁ
at ꢀ 78 C (Table 1, entry 3). As anticipated, the opposite asymmetric induction
was observed with the opposite enantiomer (Table 1, entry 4 vs 3). The analytical
1
13
data of H NMR, C NMR, nuclear Overhauser effect spectrometry (NOESY),
and high-resolution mass spectrometry (HRMS) confirmed the cyclized product as
1
a single diastereoisomer. When closely observing H NMR of 4, the upfield doublet
of doublets of C-7a proton at 4.38 ppm with Jae ¼ 4.1 Hz and Jaa ¼ 7.5 Hz and
triplet of C-7 proton at 4.42 ppm with Jae ¼ 4.1 Hz, and space interaction of proton
in NOESY do not furnish a valuable clue about the stereochemistry of 3 at the ring
juncture. Fortunately, single-crystal x-ray analysis of (ꢀ)-3 has revealed a cis-fused
chair conformation of cyclohexane with an axial iodine substituent and defined its
absolute configuration as (3aS,7aR,7R) (Fig. 1).
Subsequently, the absolute configurations of 2 and 1 were established on the
basis of (3aS,7aR,7R)-3. Therefore, dehalogenation of (3aS,7aR,7R)-3 was
ꢁ
accomplished by reduction with Bu SnH in toluene at 80 C yielding (3aS,7aS)-2
3
in 100% yield (Scheme 1). This dehalogenated product (3aS,7aS)-2 has the same
retention time on chiral high-performance liquid chromatography (HPLC) spectra
and rotation value with (ꢀ)-2 prepared by TfOH-catalyzed cyclization of (ꢀ)-1
(
Table 1, entry 1), confirming the absolute configuration of cyclized product (ꢀ)-2
as (3aS,7aS) and the starting material (ꢀ)-1 as (S). To the best of our knowledge,
this is the first report of highly enantioselective and diastereoselective cycloetherifica-
tion and cyclohaloetherification of cyclic alkenol.
Under optimized reaction conditions, enantiopure bromide 4 was obtained in
good yield as single diastereoisomer from N-bromosuccinimide (NBS) (Table 1,
entry 5). While no reaction occurred with N-chlorosuccinimide (NCS) after 24 h even
at room temperature, moderate yield of chloro product 5 was obtained with active
1
make this reaction more unique, exotic, and useful because of the fascinating
,3-dichloro-5,5-dimethylhydantoin 6 (Table 1, entry 7). Introduction of halogens
[
14]
versatility of chiral halides for many chemical transformations.
Figure 1. Single-crystal structure of (3aS,7aR,7R)-3.

118
M. SOHAIL ET AL.
3
Scheme 1. Deiodination of (3aS,7aR,7R)-3 by Bu SnH.
Finally, the mechanism of this highly diastereoselective reaction has been
hypothesized as follows. Intramolecular haloetherificatoin of 1 occurred in a
concerted 5-Trig-exo closing way. First, the activation of alcoholic substrate by
NIS (e.g., to form hypoiodite 1a), is followed by intermolecular iodine transfer from
0
in situ–generated hypoiodite 1a or 1c species at C3 position. This transfer occurs at
0
the C3 b-Si face of C=C of cyclohexene moiety. This relocation coupled with an
0
intramolecular anti addition of the pendant alcoholic oxygen to alkenyl of C2 a-
Re face at C2 results in this 100% diastero- and enantiomerically pure
(
0
0
3aS,7aR,7R)-3 (Scheme 2). Similarly, iodine transfer at C3 b-Re face of C=C of
c-hexene moiety in (R)-1 and the opposite enantiomer (3aR,7aS,7S)-3 was obtained.
In conclusion, an efficient and convenient route has been developed for the
asymmetric synthesis of optically pure octahydrobenzofurans with three contiguous
chiral centers, where the stereospecific ring closure reaction can be applied in the
0
total synthesis of imperative molecule. The chiral center at C-1 is not only incorpor-
ated into the ring system but also serves to control the stereochemistry of the rest
Scheme 2. Proposed reaction mechanism of cylohaloetherification.

ASYMMETRIC SYNTHESIS OF OCTAHYDROBENZOFURAN
119
stereogenic centers. The absolute configurations of all compounds have been
established on the basis of x-ray analysis of a single crystal. Further investigations
should be focused on application of this method to the asymmetric synthesis of some
interesting compounds.
EXPERIMENTAL
HRMS was recorded on a Bruker Apex IV FTMS. Enantiomeric excesses were
determined by chiral HPLC on a Shimadzu LC-20A apparatus with Chiralpak AS-H
1
and OD-H. H NMR spectra were recorded on a Bruker Avance 600 and Varian
1
3
Mercury 400. C NMR was recorded on a Varian Mercury 400 (100 MHz) with
complete proton decoupling. Optical rotations were measured on a Kr u¨ ss P8000
polarimeter in CH Cl .
2
2
Synthesis of Enantiopure (3aS,7aR,7R)-3
NIS (13.5 mg, 0.06 mmol, 1.2 equiv) was added to a solution of alcohol (S)-1
ꢁ
(
13.9 mg, 0.05 mmol) in CH Cl (0.5 mL) at ꢀ 78 C. The reaction mixture was stirred
2
2
ꢁ
at ꢀ 78 C for 2.5 h. After reaction completion, as monitored by thin-layer chroma-
tography (TLC), the crude product was directly loaded on column and purified by
flash column chromatography (silica gel, 200–300 mesh; Et O–petroleum ether,
2
ꢁ
1
:40, v=v) to give white transparent crystals (20 mg, 99%). Mp 104–105 C (from
1
n-hexane). H NMR (600 MHz, CDCl ) d ¼ 7.36 (d, J ¼ 7.5 Hz, 2H, Ph-H), 7.29
3
(
d, J ¼ 7.5 Hz, 2H, Ph-H), 7.28–7.23 (m, 2H, Ph-H), 7.17–7.13 (m, 4H, Ph-H),
4
7
6
.77 (d, J ¼ 8.2 Hz, 1H, 2-H ), 4.66 (d, J ¼ 8.2 Hz, 1H, 2-H ), 4.56–4.53 (m, 2H,
a
b
=7a-H), 3.38–3.35(m, 1H, 3a-H), 1.90–1.87 (m, 1H, 6a-H), 1.82–1.76 (m, 1H,
b-H), 1.72–1.64 (m, 2H, 5-H), 1.38–1.36 (m, 1H, 4a-H), 1.16–1.13 (m, 1H, 4b-H).
1
3
C NMR (100 MHz, CDCl ) d ¼ 145.8, 143.4, 128.8, 128.4, 128.1, 126.8, 126.5,
3
1
4
26.3, 82.5, 76.3, 58.8, 41.2, 33.2, 30.5, 25.0, 21.5. HRMS calcd. for C H IO:
2
0
21
þ
27.0529 (MþNa) , found: 427.0534. Both enantiomers were recognized by
ꢀ
1
chiral HPLC on OD-H (n-hexane=i-propanol ¼ 90=10, V=V, 1.0 mL min
,
2
8
2
(
54 nm), t
3aS,7aR,7R)-3).
¼ 5.54 min, t
¼ 9.97 min; [a] ¼ ꢀ 126.6 (c ¼ 0.15, CH Cl for
RSS
SRR
D
2
2
Crystal Data for (3as,7ar,7r)-3 (C H IO)
20 21
˚
M ¼ 403.76, momoclinic, P2(1), a ¼ 6.1252(10), b ¼ 22.600(4), c ¼ 24.191(4)A,
ꢁ
b ¼ 90.067(2) , Z ¼ 8. Reflections collected=unique 29745=16218, R ¼ 0.0424,
int
R ¼ 0.0616, wR ¼ 0.1370 for (I > 2r(I), R ¼ 0.0720, wR ¼ 0.1434. For details,
1
2
1
2
see CCDC 903689.
SUPPORTING INFORMATION
1
13
Experimental procedures, H and C NMR spectra, HPLC spectra, and x-ray
analysis can be found via the Supplementary Content section of this article’s Web
page.

120
M. SOHAIL ET AL.
ACKNOWLEDGMENTS
Financial support from Beijing Institute of Technology (2011CX01008 and
others), Chinese Scholarship Council (M. Sohail), and NSFC (20972016) are
acknowledged.
REFERENCES
1
. (a) Procter, G.; Stereoselectivity in Organic Synthesis; Oxford Science: Oxford, 1998;
b) Guindon, Y.; Soucy, F.; Yoakim, C.; Ogilvie, W. W.; Plamondon, L. J. Org. Chem.
001, 66, 8992.
(
2
2
. (a) Dulcere, J. P.; Mihoubi, M. N.; Rodriguez, J. J. Org. Chem. 1993, 58, 5709; (b) Okabe,
M.; Abe, M.; Tada, M. J. Org. Chem. 1982, 47, 1775; (c) Lin-Gen, Z.; Seligmann, O.;
Lotter, H.; Wagner, H. Phytochemistry 1983, 22, 265; (d) Duh, C.-Y.; Phoebe, C. H.,
Jr.; Pezzuto, J. M.; Kinghorn, A. D.; Farnsworth, N. R. J. Nat. Prod. 1986, 49, 706.
. (a) Huang, J.; Chen, F.-E. Helv. Chim. Acta 2007, 90, 1366; (b) Arimitsu, K.; Nomura, S.;
Iwasaki, H.; Ozeki, M.; Yamashita, M. Tetrahedron Lett. 2011, 52, 7046; (c) Trost, B. M.;
Shen, H. C.; Surivet, J.-P. J. Angew. Chem. Int. Ed. 2003, 42, 3943.
3
4
. (a) Baguley, P. A.; Walton, J. C. J. Chem. Soc., Perkin Trans. 1 1998, 13, 2073;
(
(
b) Baguley, P. A.; Jackson, L. V.; Walton, J. C. J. Chem. Soc., Perkin Trans. 1 2002, 304;
c) Periasamy, M.; Ponnuswamy, A. J. Heterocycl. Chem. 2007, 44, 883.
5. Clive, D. L. J.; Chittattu, G. J.; Farina, V.; Kiel, W. A.; Menchen, S. M.; Russell, C. G.;
Singh, A.; Wong, C. K.; Curtis, N. J. J. Chem. Soc. 1980, 102, 4438.
6. Yakura, T.; Yamada, S.; Shima, M.; Iwamoto, M.; Ikeda, M. Chem. Pharm. Bull. 1998,
46, 744.
7
8
. Ferraz, H. M. C.; Longo, L. S., Jr. J. Org. Chem. 2007, 72, 2945.
. Herrinton, P. M.; Hopkins, M. H.; Mishra, P.; Brown, M. J.; Overman, L. E. J. Org.
Chem. 1987, 52, 3711.
9. (a) Groves, J. T. Tetrahedron Lett. 1975, 16, 3113; (b) Motohashi, S.; Satomi, M.;
Fujimoto, Y.; Tatsuno, T. Heterocycles 1985, 23, 2035.
10. Qian, H.; Han, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 9536.
11. McKinney Brooner, R. E.; Widenhoefer, R. A. Chem.—Eur. J. 2011, 17, 6170.
12. Sohail, M.; Wang, Y.-F.; Wu, S.; Guo, J.; Zen, W.; Chen, F.-X. Chinese J. Chem. Lett.
2013, 24, 495.
1
1
3. Goulombel, L.; Dunach, E. Green Chem. 2004, 6, 499.
4. (a) Terao, J.; Kambe, N. Acc. Chem. Res. 2008, 41, 1545; (b) Yin, H.; Zhao, C.; You, H.;
Lin, K.; Gong, H. Chem. Commun. 2012, 48, 7034; (c) Suarez, A. R.; Martin, S. E.;
Martinelli, M.; Domine, M. E.; Mazzieri, M. R. Tetrahedron 1998, 54, 7375; (d)
Chaturvedi, D.; Chaturvedi, A. K.; Mishra, N.; Mishra, V. J. Iran. Chem. Soc. 2009, 6,
510; (e) Yoshida, S.; Yorimitsu, H.; Oshima, K. Chem. Lett. 2009, 38, 248; (f) Sai, M.;
Someya, H.; Yorimitsu, H.; Oshima, K. Org. Lett. 2008, 10, 2545.