Bio-inspired polyene cyclization: Synthesis of tetracyclic terpenoids promoted by steroidal acetal-SnCl4

Article abstract of DOI:10.1039/b714474a

This communication describes a highly efficient intermolecular polyene cyclization method using steroidal acetals as the initiators to synthesize tetracyclic terpenoids; both good yields and good asymmetric induction were obtained. The Royal Society of Chemistry.

Full text of DOI:10.1039/b714474a

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COMMUNICATION
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Bio-inspired polyene cyclization: synthesis of tetracyclic terpenoids
promoted by steroidal acetal–SnCl4w
Yu-Jun Zhao and Teck-Peng Loh*
Received (in Bloomington, IN, USA) 19th September 2007, Accepted 7th January 2008
First published as an Advance Article on the web 24th January 2008
DOI: 10.1039/b714474a
This communication describes a highly efficient intermolecular
polyene cyclization method using steroidal acetals as the initia-
tors to synthesize tetracyclic terpenoids; both good yields and
good asymmetric induction were obtained.
Multiple ring formation using polyene cyclization reactions is
a powerful method for the preparation of alicyclic com-
pounds.1,2 A host of examples of polyene cyclization reactions
for the synthesis of bicyclic and tricyclic compounds have been
established, but reactions for forming tetracyclic compounds
and above are still rare.1–3 Furthermore, polyene cyclization
reactions are attractive for the synthesis of molecules contain-
ing highly substituted C–C bonds.1,2 Recently, Yamamoto
et al. have demonstrated that chiral LBA (Lewis acid-assisted
Brønsted acid) catalysts can be used to construct multiple rings
with high enantioselectivities.4 Ishihara et al. have also ele-
gantly established a highly enantioselective polyene cyclization
reaction promoted by a chiral electrophilic halogen atom.5g
Scheme 1 The formation of tetracyclic terpenoids using PhCHO
chiral acetal.z
However, using polyene cyclization reactions to construct
molecules containing more than three rings continues to pose
a challenge to organic chemists. Herein, we describe the
application of our previously reported approach6 to a more
challenging synthetic problem by using chiral aldehyde acetal
and chiral acetal as a template to promote diastereoselective
cyclization of polyprenoids to form tetracyclic terpenoids.
In the presence of SnCl4, it was found that chiral acetal A
Scheme 2 Modification of bicyclic cyclization isomers.
promoted polyene 1 to furnish tetracyclic compound 2 with
good yield and moderate diastereoselectivity (71% yield, dr:
48 : 15 : 30 : 7)7,8 (see Scheme 1). The cyclization product can
be easily modified to afford terpenoid 6 and 3-azaterpenoid5 8
with good enantioselectivity (6, 46% ee; 8, 46% ee). In
addition, the bicyclic isomer product 30 can also be easily
converted to the desired product 7 as shown in Scheme 2.
Next, we carried out the polyene cyclization reaction using
chiral steroidal aldehyde B (StCHO) acetal as the initiator. To
Scheme 3 Cyclization promoted by steroidal acetal as the initiating
group.z
our delight, it was found that the oxonium generated from the
aliphatic acetal was also efficient in initiating the cyclization of
polyene 9. The desired product 10a was obtained in excellent
Further investigation showed that this cyclization method
yield (80%) with good diastereoselectivity (87 : 11 : 2) (see
can also be applied to longer chain polyprenoid substrates to
Scheme 3).
construct tetracyclic terpene skeletons (refer to Table 1). With
different substituents on the benzene ring, all cyclization
products were obtained in good yields and moderate di-
Division of Chemistry and Biological Chemistry, School of Physical
astereoselectivities.
and Mathematical Sciences, Nanyang Technological University, 1
Nanyang Walk, Block 5 level 3 Singapore 639798. E-mail:
teckpeng@ntu.edu.sg; Fax: +65 6791 1961; Tel: +65 6316 8899
w Electronic supplementary information (ESI) available: Detailed
experimental procedures, 1H NMR, 13C NMR and analytical data
for all compounds. See DOI: 10.1039/b714474a
For mechanistic interest, we further proceeded to investigate
the effect of chirality of the 1,3-dioxane moiety on the cycliza-
tion diastereoselectivity. Therefore, the reactions were carried
out using different steroidal acetals (C and D) with opposite
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Table 1 Cyclization with different substituents on benzene substrates
using steroidal acetal templatez
Entry
R
Product
Yield (%)a
drb
1
2
3c
4
5
6
a
—
11
73
66
75
76
59
71
66 : 18 : 10 : 6
66 : 17 : 14 : 3
73 : 14 : 12 : 1
71 : 20 : 8 : 1
74 : 18 : 7 : 1
64 : 20 : 14 : 2
b
4-Me
3-Me
2-Me
4-OMe
4-iPr
11c
11d
11e
11f
11g
Isolated yield of four isomers after flash chromatography. Cycliza-
tion products were converted to corresponding aldehydes, the values
of dr were determined based on the integration ratio of CHO peaks in
the 1H NMR spectra. No regioisomers of the benzene ring were
detected.4b
c
Scheme 5 (Top) Verification of the steroidal aldehyde template
effect.z (Bottom) Representative X-ray crystallographic structure of
the major isomer of 12b. The ellipsoids are shown at the 50%
probability level.9
chirality on the 1,3-dioxane moiety (see Scheme 4). To our
surprise, the absolute stereochemistries of both cyclization
products shared the same trend, despite the chirality of the
1,3-dioxane moiety in the acetal being opposite. This result
suggested that the chirality of the steroidal aldehyde played a
dominant role in the control of the stereochemistry of the
cyclization. It is worth noting that cyclization products and
their derivatives can be obtained in optically pure isomers after
single recrystallization (10b0, 40% yield; 10c, 30% yield).
Extension of this method to the polyene cyclization of 1
afforded the tetracyclic products in moderate yields (11a, 45%;
11b, 50%). Similar stereochemistries were observed for both
12a and 12b. This confirmed that the chirality of the steroidal
aldehyde played a vital role in the control of the stereochem-
istry of the cyclization. It was notable that a single recrystalli-
zation of the oxidation product 12b afforded the optically pure
isomer in 28% yield (see Scheme 5).
The cyclization products promoted by steroidal acetal–SnCl4
are unique as the two biomolecules, steroid and terpenoid, are
connected together through a C–C bond. It is also notable that
cyclization products are versatile intermediates which can be
readily converted to diverse tetracyclic terpenoids compounds
bearing the steroid moiety as shown in Scheme 6.
Scheme 6 Functionalization of a cyclization product.10
In conclusion, we have reported a diastereoselective inter-
molecular polyene cyclization mediated by steroidal acetal–
SnCl4 to construct multiple ring terpene skeletons. The pro-
ducts were obtained in good yields and good diastereoselec-
tivities. Investigations into diverse syntheses with different
chiral templates and the application of this method to the
total syntheses of natural products are in progress.
We thank Dr Yong-Xin Li for X-ray analyses. We gratefully
acknowledge the Nanyang Technological University and the
Singapore Ministry of Education Academic Research Fund
Tier 2 (No. T206B1221) for the financial support of this
research.
Scheme 4 (Top) Chiral induction comparison between 1,3-dioxane
and aldehyde chirality.z (Bottom) X-Ray crystallographic structures
of the major isomers of 10b0 (left) and 10c (right). The ellipsoids are
shown at the 50% probability level.9
Notes and references
z Representative procedure: steroidal aldehyde–SnCl4 promoted acetal
cyclization reactions: to a solution of alkene 9 (22.4 mg, 0.1 mmol, 1.0
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eq.) in DCM (2 mL) was added acetal B (78.0 mg, 0.2 mmol, 2.0 eq.) at
room temperature. The solution was cooled to ꢁ78 1C prior to the
addition of SnCl4 (1.0 M in DCM, 0.2 mL, 2.0 eq.). The reaction was
allowed to stir at ꢁ78 1C for 24 h before quenching with saturated
NaHCO3 aqueous solution (5 mL). The mixture was gradually
warmed up to room temperature and was allowed to stir for another
1 h. The aqueous layer was extracted with DCM (3 ꢂ 20 mL), and the
combined organic layer was washed with water (20 mL), brine (20 mL)
and dried over anhydrous Na2SO4, filtered and concentrated in vacuo.
The residual crude product was purified by flash column chromato-
graphy to afford desired product 10a as a white solid in 80% yield
(mixture of isomers). Isomer ratio: 87 : 11 : 2 (based on derivate
aldehyde 1H NMR integration). Rf: 0.18 (hexane–ethyl acetate, 4 : 1).
1 J. K. Sutherland, in Comprehensive Organic Synthesis, ed.
B. M. Trost, Pergamon Press, Oxford, 1991, vol. 5, ch. 1.9,
p. 341.
2 P. A. Bartlett, in Asymmetric Synthesis, ed. J. D. Morrison,
Academic Press, New York, 1984, vol. 3, p. 341.
3 (a) W. S. Johnson, Tetrahedron, 1991, 47, xi–1; (b) E. J. Corey and
H. B. Wood, Jr, J. Am. Chem. Soc., 1996, 118, 11982–11983 and
references therein; ; (c) M. Demuth, U. Hoffmann, Y. M. Gao, B.
Pandey, S. Klinge, K. D. Warzecha, C. Kruger and H. D. Roth, J.
Am. Chem. Soc., 1993, 115, 10358–10359; (d) C. Heinemann and
M. Demuth, J. Am. Chem. Soc., 1997, 119, 1129–1130; (e) E. E.
van Tamelen and J. R. Hwu, J. Am. Chem. Soc., 1983, 105,
2490–2491 and references therein.
4 (a) H. Yamamoto, K. Ishihara and H. Ishibashi, J. Am. Chem.
Soc., 2004, 126, 11122–11123; (b) H. Yamamoto, K. Ishihara and
H. Ishibashi, J. Am. Chem. Soc., 2002, 124, 3647–3655; (c) H.
Yamamoto, S. Nakamura and H. Ishibashi, J. Am. Chem. Soc.,
1999, 121, 4906–4907 and references therein.
5 3-Heteroatom terpenoids are widely distributed in nature and some
of these compounds have very interesting biological activities.
Some references: (a) F. Lv, Z. W. Deng, J. Li, H. Z. Fu, R. W.
M. van Soest, P. Proksch and W. H. Lin, J. Nat. Prod., 2004, 67,
2033–2036; (b) D. Tasdemir, G. C. Mangalindan, G. P. Concep-
cion, S. M. Verbitski, S. Rabindran, M. Miranda, M. Greenstein,
J. N. A. Hooper, M. K. Harper and C. M. Ireland, J. Nat. Prod.,
2002, 65, 210–214; (c) B. M. Fraga, Nat. Prod. Rep., 2006, 23,
943–972 and references therein; (d) J. R. Hanson, Nat. Prod. Rep.,
2006, 23, 875–885 and references therein; (e) D. Abramson, F. F.
Knapp, L. J. Goad and T. W. Goodwin, Phytochemistry, 1977, 16,
1935–1937; (f) S. Ijichi and S. Tamagaki, Chem. Lett., 2005, 34,
356–357. For recent progress in the asymmetric cyclization of 3-
bromo and 3-iodo terpenoids, see: ; (g) A. Sakakura, A. Ukai and
K. Ishihara, Nature, 2007, 445, 900–903.
6 Y. J. Zhao, S. S. Chng and T. P. Loh, J. Am. Chem. Soc., 2007,
129, 492–493.
7 dr = diastereoisomer ratio. For Scheme 1 dr were reported as the
benzylic isomer ratio based on 1H NMR integration of benzylic
CHs.
8 For Scheme 1, diastereomers here refer to isomers with different
relative configuration between the chiral center(s) on the benzylic
carbon and the five new chiral centers formed in the tricyclic
skeleton. The five new chiral centers formed are considered as
one chiral group (of fixed relative configuration within the group)
based on the Stork–Eschenmoser postulate. See: (a) G. Stork and
A. W. Burgstahler, J. Am. Chem. Soc., 1955, 77, 5068; (b) A.
Eschenmoser, L. Ruzicka, O. Jeger and D. Arigoni, Helv. Chim.
Acta, 1955, 38, 1890. For all other cases, the assignment of
diastereoisomers for Scheme 1 applied as well.
1
Major isomer: H NMR (500 MHz, CDCl3): 7.38–7.02 (m, 4H), 5.75
(s, 1H), 3.90–3.70 (m, 3H), 3.70–3.50 (m, 1H), 3.45–3.35 (m, 1H), 2.97
(dd, J = 17.03, 5.58 Hz, 1H), 2.90–2.80 (m, 1H), 1.23 (s, 3H), 1.20 (s,
3H), 1.20 (s, 3H), 0.95 (d, J = 6.80 Hz, 3H), 0.94 (s, 3H), 0.72 (s, 3H).
13C NMR (100 MHz, CDCl3): 199.7, 171.6, 149.9, 135.0, 128.8, 125.7,
125.2, 124.5, 123.8, 80.6, 72.5, 63.1, 55.8, 53.7, 53.6, 53.3, 52.2, 45.1,
42.4, 39.6, 39.0, 38.6, 37.8, 37.3, 35.7, 35.7, 34.0, 32.9, 32.4, 32.0, 30.8,
29.5, 28.6, 25.2, 24.3, 21.0, 20.9, 19.2, 18.0, 17.4, 12.7, 11.7. HRMS
(CI): m/z calculated for C42H62O3 [M]+: 614.4699, found [M ꢁ H]+
:
613.4521. FTIR (NaCl): n 3436 (b), 1658, 1616, 1448, 1436, 1377, 1265,
1230 cmꢁ1
.
Oxidation of cyclization products: To an oven-dried round-bottomed
flask equipped with a magnetic stirring bar was added pyridinium
chlorochromate (PCC) (65 mg, 0.3 mmol, 3.0 eq.), 4 A molecular
sieves (0.1 g), silica gel (0.1 g) and DCM (10 mL). A solution of alcohol
10a (61 mg, 0.1 mmol, 1.0 eq. in 5 mL of DCM) mixture was added
via syringe at 0 1C. The mixture was allowed to warm up to room
temperature and stirred for 12 h until the reaction had finished.
The reaction solution was filtered through a pad of silica gel packed
in a sintered funnel and washed with ethyl acetate (100 mL). The
filtrate was concentrated in vacuo. The residual crude product was
purified by flash column chromatography to afford aldehyde 10a0 as a
white solid in 80% yield. Isomer ratio: 87 : 11 : 2 (CHO 1H NMR
integration) Rf: 0.23 (hexane–ethyl acetate, 4 : 1). Major isomer: 1H
NMR (400 MHz, CDCl3): 9.84 (t, J = 2.07 Hz, 1H), 7.29–7.22 (m,
1H), 7.16–7.09 (m, 1H), 7.09–7.00 (m, 2H), 5.73 (s, 1H), 3.87 (dt, J =
8.60, 5.87 Hz, 1H), 3.74 (dt, J = 9.12, 6.40 Hz, 1H), 3.42 (m, 1H), 2.95
(dd, J= 16.78, 5.87 Hz, 1H), 2.90–2.80 (m, 1H), 2.65–2.60 (m, 2H),
1.20 (s, 3H), 1.19 (s, 3H), 0.94 (s, 3H), 0.93 (s, 3H), 0.91 (d, J = 6.91
Hz, 3H), 0.70 (s, 3H). 13C NMR (100 MHz, CDCl3): 201.9, 199.6,
171.6, 149.9, 135.0, 128.8, 125.7, 125.2, 124.5, 123.8, 80.0, 65.6, 55.8,
53.7, 53.5, 53.3, 52.2, 45.1, 44.5, 42.4, 39.6, 39.1, 38.6, 37.8, 37.3, 35.7,
35.6, 34.0, 33.0, 32.0, 30.9, 29.5, 28.6, 25.3, 24.3, 21.0, 20.8, 19.2, 18.0,
17.4, 12.5, 11.7. HRMS (CI): m/z calculated for C42H60O3 [M]+
612.4542, found: not obtained. FTIR (NaCl): n 1654 (b), 1448, 1375,
1228, 1186, 1097 cmꢁ1
:
.
9 For 10b0, 10c, 12b: CCDC 661546, 661547 and 661548. For
crystallographic data in CIF format see DOI: 10.1039/b714474a.
10 The regioisomer ratio is reported in the ESI.w The isomerization of
the double bond was reported by De Leeuw, et al.: J. W. De
Leeuw, E. R. De Waard, T. Beetz and H. O. Huisman, Recl. Trav.
Chim. Pays-Bas, 1973, 92, 1047.
Theoretically, four possible isomers were formed (for detailed struc-
tures see ESIw). For Scheme 1, dr refers to diastereomer ratio, see ref. 7
and 8; for Scheme 3, cyclization products were converted to the
corresponding aldehyde, and the dr was determined based on the
1
integration ratio of CHO peaks in the H NMR spectra.
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1436 | Chem. Commun., 2008, 1434–1436