Synthesis of optically pure 2,3,4-trisubstituted tetrahydrofurans via a two-step sequential Michael-Evans aldol cyclization strategy: total synthesis of (+)-magnolone

Article abstract of DOI:10.1016/j.tetlet.2010.03.111

Synthesis of optically pure 2,3,4-trisubstituted tetrahydrofurans is described employing a two-step Michael-Evans aldol cyclization strategy. The approach is successfully applied for the total synthesis of furano lignan natural product (+)-magnolone.

Full text of DOI:10.1016/j.tetlet.2010.03.111

Tetrahedron Letters 51 (2010) 2975–2978
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Tetrahedron Letters
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Synthesis of optically pure 2,3,4-trisubstituted tetrahydrofurans via a two-step
sequential Michael-Evans aldol cyclization strategy: total synthesis of
(+)-magnolone
a
a
b
Ganesh Pandey a, , Srikanth Luckorse , Asha Budakoti , Vedavati G. Puranik
*
a Division of Organic Chemistry, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
b Center for Material Characterization, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of optically pure 2,3,4-trisubstituted tetrahydrofurans is described employing a two-step
Michael-Evans aldol cyclization strategy. The approach is successfully applied for the total synthesis of
furano lignan natural product (+)-magnolone.
Received 3 March 2010
Revised 25 March 2010
Accepted 28 March 2010
Available online 4 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Tetrahydrofuran
Lignans
Magnolone
HWE reaction
Michael-Evans aldol reaction
Devising newer protocols for synthesizing substituted tetra-
hydrofurans, in general, has been the focus of synthetic organic
chemists for some time owing to the presence of this core unit in
many natural products1 possessing diverse array of biological
activities.2 In particular, construction of stereo-defined optically
pure 2,3,4-trisubstituted tetrahydrofurans, representing core
structure of furano lignan class of natural products,3 has been an
attractive target. It has generally been noticed that the natural
products belonging to this class display ‘2,3-trans,3,4-trans’ stereo-
chemistry4 (e.g., sesaminone 1, magnolone 2) however, other ste-
reochemical arrangements such as ‘2,3-cis,3,4-trans’5 (e.g.,
sylvone 3) and ‘2,3-trans, 3,4-cis’ (e.g., 2,6-diaryl, 3,7-dioxabicyclo
[3,3,0] octane lignans or furofuran lignans 4)6 are also known
(Fig. 1).
rans, applicable for the synthesis of furano lignan natural products
appears to be demanding.
In this context, we envisioned that the conjugate addition to 5
followed by aldol and intramolecular cyclization sequence, as
shown in Scheme 1, may lead to stereoselective construction of tri-
substituted tetrahydrofuran skeleton efficiently. Furthermore, this
strategy was envisaged to be attractive as the desired stereochem-
istry at various centres of tetrahydrofuran could easily be tuned at
will. For illustration, the stereochemistry of R group at C-4 will de-
O
O
O
HO
HO
OCH3
OCH3
O
O
O
O
O
Recent review by Wolfe et al.7 broadly covers most of the trans-
formations related to the synthesis of tetrahydrofurans in optically
pure form, however, very few methods are known which could di-
rectly be used for the total synthesis of tetrahydrofuran lignans. It
appears that there are only two suitable methods to synthesize fur-
ano lignans which involve either the Lewis acid-mediated coupling
of cyclic allyl siloxanes with aldehydes8 or [1,3]-rearrangement of
1,3-dioxepins.9 Therefore, developing a simple, efficient and ste-
reo-divergent protocol to access 2,3,4-trisubstituted tetrahydrofu-
O
1
2
O
Sesaminone
(+)-Magnolone
OCH3
O
O
O
Ar2
HO
H
H
OCH3
OCH3
Ar1
O
H3CO
H3CO
4
3
Ar1, Ar2 = 3, 4-methylenedioxy phenyl
or 3, 4-dimethoxy phenyl
Sylvone
* Corresponding author. Tel.: +91 20 25902627; fax: +91 20 25902628.
E-mail address: gp.pandey@ncl.res.in (G. Pandey).
Figure 1. Structures of furo and furofuran lignans.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.111

2976
G. Pandey et al. / Tetrahedron Letters 51 (2010) 2975–2978
O
O
O
O
O
R
O
O
O
Michael-
Aldol
R
RMgBr, CuI,
THF
OTBS
N
N
O
N
O
O
N
O
OTBS
TBSO
TBSO
Ph
-78 ºC to rt
OH
Ph
Ph
Ar
5
8a-c
Ph
5
8
R
Yield (%)
dr
Tetrahydrofurans
Scheme 1. Synthetic strategy for substituted tetrahydrofurans.
a
b
c
Me
90
95
88
98:2
>99:1
97:3
Vinyl
Prop-1-enyl
Scheme 3. Michael addition reaction on 5.
pend upon the Evans chiral auxiliary whereas the stereochemistry
at C-2 and C-3 centres of THF ring could easily be controlled
employing either Evans syn- or anti-aldol reaction protocols.10
In this Letter, we disclose our preliminary and successful results
of a two-step strategy to construct stereo-defined 2,3,4-trisubsti-
tuted tetrahydrofurans employing Michael-Evans aldol cyclization
sequence.
O
O
R
OTi
Ar
TiCl4, DIPEA
ArCHO,
-78 ºC tort
O
O
N
O
O
N
TBSO
OTi
R
Ph
8a-c
Ph
We initiated the proposed synthesis of 2,3,4-trisubstituted tetra-
hydrofurans by carrying out first one-pot Michael-aldol-cyclization
sequence starting from 5 (Scheme 2). Compound 5 was easily pre-
pared in 85% yield by Horner–Wadsworth–Emmons reaction11 of
phosphonate12 6 with 2-(tert-butyldimethylsiloxy) acetaldehyde13
in the presence of K2CO3. Compound 5 upon treatment with a solu-
tion of alkyl magnesium bromide (1.2 equiv) and CuI (1.5 equiv) in
THF (ꢀ78 °C to rt) followed by sequential addition of p-anisaldehyde
(1.2 equiv) and TiCl4 (2 equiv) at ꢀ78 °C gave corresponding insepa-
rable mixture of diastereomeric tetrahydrofurans.
This observation led us to examine the diastereomeric purity of
the Michael-aldol reaction product 7, which was found to be a mix-
ture (dr 7:3, determined by 1H NMR). Therefore, we decided to
adopt two-step protocol from 5 to obtain substituted THFs. Mi-
chael addition (Scheme 3) of various organocuprates (prepared
by mixing corresponding Grignard reagent (1.2 equiv) and dry
CuI (1.5 equiv) in THF at ꢀ78 °C) to 5 gave corresponding conjugate
adducts 8a–c with very high diastereomeric purity14,15 (see
Scheme 3), determined by HPLC (mobile phase: MeOH/H2O
(90:10), flow rate: 1.0/min, column: Grace Denali RP-18 (250 ꢁ
4.6 mm)) analysis. Pure diastereomers were easily separated by
column chromatography (Silica Gel 100–200, eluent: ethyl ace-
tate/pet ether (5:95)).
O
O
O
Aux*
R
O
Ar
OTi
O
N
R
Ar
9a-e
Ph
R
ArCHO
9
Yield(%)
8a
8b
8c
Me
Vinyl
Prop-
1-enyl
p-anisaldehyde
p-anisaldehyde
p-anisaldehyde
a
b
c
72
80
67
8b
8c
Vinyl
Prop-
1-enyl
piperonal
piperonal
d
e
82
78
Scheme 4. Synthesis of tetrahydrofurans using Evans syn-aldol reaction.
The relative stereochemistry of the substituents in 9c was as-
signed by detailed 2D NMR spectroscopy (COSY and NOESY) and fi-
nally confirmed by single crystal X-ray analysis (Fig. 2).17 The
inverted stereochemistry at C-2 benzylic carbon suggests that tet-
rahydrofuran ring formation involved thermodynamically fa-
Reaction of diastereomerically pure 8c with TiCl4 (2.5 equiv),
DIPEA (3 equiv) and p-anisaldehyde (1.2 equiv) in DCM at ꢀ78 °C
(Evans syn-aldol reaction condition) (Scheme 4) followed by usual
work-up and purification gave, to our delight, diastereomerically
pure 2,3-trans, 3,4-trans trisubstituted tetrahydrofuran 9c in 67%
yield.16
1
voured intramolecular SN type nucleophilic substitution at
benzylic position. In order to study the generality of this reaction,
various reactions combining different aldehydes and conjugate ad-
ducts (8a–c) were carried out and the results are presented in
Scheme 4.
With these successful results, we decided to apply this protocol
for the total synthesis of tetrahydrofuran lignan natural product
(+)-magnolone18 (2). Compound 2 is a trisubstituted 70-oxo tetra-
hydrofuran lignan isolated from the leaves of magnolia coco. and
has been used in the treatment of impaired liver function and
cancer.
O
O
O
TBSO
O
O
P
O
R
OMe
OMe
K2CO3, DCM
N
O
N
O
0 ºC to rt, 9h
85%
OTBS
Yamauchi and Nakato19 have synthesized this molecule
employing erythro selective aldol condensation followed by a ster-
eoselective intramolecular SN cyclization in the presence of acid
catalyst starting from (S)-benzyl-3-pent-4-enoyloxazolidin-2-one,
and also assigned the absolute configuration as (7S,8R,8’S).
Ph
Ph
6
5
1
O
1. RMgBr, CuI
OTBS
THF,-78 ºC to rt
Aux*
OH
We began the synthesis of 2 starting from tetrahydrofuran
derivative 9d. LiBH4 reduction of 9d in THF at 0 °C followed by pro-
tection of primary alcohol moiety as –OTBS provided 10 in 98%
yield. Dihydroxylation of 10 using OsO4 (cat.), trimethyl amine
N-oxide (TMO, 1.2 equiv), in THF/t-BuOH/H2O (2:4:1) gave corre-
sponding diol which on cleavage using NaIO4 (1.2 equiv) in THF/
H2O (2:1) provided corresponding aldehyde 11 in 90% yield. Reac-
tion of 11 with 4-lithio-1,2-dimethoxy benzene (1.2 equiv) in THF
2. ArCHO, -78 ºC to rt
3.TiCl4
Ar
dr: 7:3, R = vinyl
7
O
R
Aux*
Ar
O
Scheme 2. Initial strategy for tetrahydrofurans.

G. Pandey et al. / Tetrahedron Letters 51 (2010) 2975–2978
2977
O
O
O
O
N
Ph
9c
MeO
Figure 2. ORTEP diagram of 9c. Ellipsoids are drawn at 40% probability.
2. (a) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504; (b) Zafra-
Polo, M. C.; Figadere, B.; Gallardo, T.; Tormo, J. R.; Cortes, D. Phytochemistry
1998, 48, 1087.
3. Ward, R. Nat. Prod. Rep. 1999, 16, 75.
4. Chiung, Y. M.; Hayashi, H.; Matsumoto, H.; Otani, T.; Yoshida, K.; Huang, M. Y.;
Chen, R. X.; Liu, J. R.; Nakayama, M. J. Antibiot. 1994, 47, 48.
OTBS
O
O
1. LiBH4, THF
0 ºC-rt, 3h, 95%
2.TBSCl, Im,
DMF, rt, 9h,
98%.
N
O
Ar
O
Ar
O
10
9d
Ph
5. Banerji, A.; Sarkar, M.; Ghosal, T.; Pal, S. C.; Shoolery, J. N. Tetrahedron 1984, 40,
5047.
TBSO
6. Brown, R. C. D.; Swain, N. A. Synthesis 2004, 6, 811.
H
1. OsO4, NMO,
t-BuOH, H2O,
THF, 6h, 92%
7. Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261. and references cited there in.
8. Miles, S. M.; Marsden, S. P.; Leatherbarrow, R. J.; Coates, W. J. J. Org. Chem. 2004,
69, 6874.
O
4-Lithio-1 ,2-dimethoxy
benzene, THF,
-78 ºC to 0 ºC
70% (2 steps)
2. NaIO4, H2O,
THF, 0 ºC, 5h,
90%
9. Nasveschuk, C. G.; Jui, N. T.; Rovis, T. Chem. Commun. 2006, 3119.
10. For Evans syn- and anti-aldol reactions see: (a) Evans, D. A. Aldrichim. Acta
1982, 15, 23; (b) Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichim. Acta 1997, 30, 3;
(c) Evans, D. A.; Bartoli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127; (d)
Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem. Soc. 1991, 113,
1047; (e) Nerz-Stormes, M.; Thornton, E. R. J. Org. Chem. 1991, 56, 2489; (f)
Bonner, M. P.; Thorton, E. R. J. Am Chem. Soc. 1991, 113, 1299; (g) Crimmins, M.
T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem. 2001, 66, 894; (h) Evans,
D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2002, 124, 392.
11. (a) Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733; (b)
Wadsworth, W. S., Jr.; Emmons, W. D. Org. Synth. 1973, Coll. Vol. 5, 547; (c)
Wadsworth, W. S., Jr. Org. React. 1977, 25, 73.
O
11
Ar
OMe
OH
OTBS
1. IBX, EtOAc
reflux, 7h
OMe
(+)-2
2.TBAF, THF
90% 2 steps
O
Ar
12
Scheme 5. Total synthesis of (+)-magnolone.
12. Evans, D. A.; Johnson, J. S. J. Org. Chem. 1997, 62, 786. Supplementary data.
13. Azumaya, I.; Uchida, D.; Kato, T.; Yokoyama, A.; Tanatani, A.; Takaynagi, H.;
Yokozuwa, T. Angew. Chem. 2004, 116, 1384.
at ꢀ78 °C gave 12 in 70% yield. Oxidation of 12 using IBX (2 equiv)
in refluxing ethyl acetate followed by TBS deprotection (TBAF,
1.2 equiv/THF) gave 2 in 44% overall yield starting from 9d. The
14. (a) Schneider, O.; Reese, O. Synthesis 2000, 1689; (b) Qian, X.; Russel, K. C.;
Boteju, L. W.; Hruby, V. J. Tetrahedron 1995, 51, 1033; (c) Lou, B.-S.; Li, G.; Lung,
F.-D.; Hruby, V. J. J. Org. Chem. 1995, 60, 5509; (d) Nicolas, E.; Russel, K. C.;
Hruby, V. J. J. Org. Chem. 1993, 58, 766.
spectral data of 2 (½a D29:4
ꢂ
+23.5 (c 0.15, CHCl3), Lit.18
½
a 2D0
+31 (c
ꢂ
15. Data for conjugate adduct 8c: thick colourless liquid. ½a D27:4
ꢂ
+30.26 (c 1.0,
0.2, CHCl3)) were found to be in excellent agreement with those
of literature values reported for (+)-magnolone (Scheme 5).
In conclusion, we have developed a concise and stereo-diver-
gent method for the synthesis of optically pure 2,3,4-trisubstituted
tetrahydrofurans. The significance of this strategy is successfully
demonstrated by applying for the total synthesis of furo lignan
(+)-magnolone. Total synthesis of other similar furo lignans is in
progress.
CHCl3). IR (neat) vmax; 3027, 2955, 2857, 1783, 1702, 1647, 1604, 1497, 1471,
1387, 1353, 1256, 1216, 1100, 1005, 938, 895, 837, 758, 701, 666 cmꢀ1 1H
.
NMR (200 MHz, CDCl3) 7.17–7.36 (m, 5H), 4.71–4.86 (m, 2H), 4.59–4.71 (m,
1H), 4.14–4.17 (m, 2H), 3.68 (dd, J = 5.44, 9.73 Hz, 1H), 3.52 (dd, J = 7.33,
9.73 Hz, 1H), 3.30 (dd, J = 2.91, 13.14 Hz, 1H), 3.14–3.18 (m, 2H), 2.80–2.88 (m,
1H), 2.70 (dd, J = 9.86, 13.52 Hz, 1H), 1.79 (s, 3H), 0.89 (s, 9H), 0.05 (s, 6H). 13C
NMR (50 MHz, CDCl3), 172.3, 153.4, 145.4, 135.2, 129.4, 128.8, 127.2, 111.6,
65.9, 65.4, 55.1, 44.8, 37.8, 36.0, 25.8, 21.6, 18.2, ꢀ5.4. Mass (ESI-MS); m/z
440.62 (M+Na)+. Anal. Calcd for C23H35NO4Si: C, 66.15; H, 8.45; N, 3.35; O,
15.32; Si, 6.73. Found: C, 66.11; H, 8.40; N, 3.25.
16. General procedure for the Evans syn-aldol cyclization reaction: To a solution of
conjugate adduct (e.g., 8c) (2.50 mmol) in dry DCM (15 mL) at ꢀ78 °C was
added dropwise TiCl4 (6.30 mmol), followed by DIPEA (7.50 mmol). The
mixture was allowed to stir at this temperature for 30 min. Aldehyde
(3.0 mmol) in DCM (8 mL) was added dropwise at ꢀ78 °C and the mixture
slowly warmed up to rt. The reaction was quenched with aqueous solution of
NH4Cl. DCM layer separated, aqueous layer was extracted with DCM
(2 ꢁ 10 mL) and the combined organic layers were dried over Na2SO4 and
concentrated under reduced pressure. The resultant residue was purified by
column chromatography to obtain substituted tetrahydrofurans (e.g., 9c) in
good yields.
Acknowledgements
L.S.K. and B.A. thank CSIR, New Delhi, for the award Research
Fellowships. The support of DST for funding our research pro-
gramme is also greatly acknowledged.
References and notes
Data for substituted tetrahydrofurans 9c: mp 121–123 °C. ½a D26:5
ꢀ25.28 (c 1.0,
ꢂ
1. (a) Faul, M. M.; Huff, B. E. Chem. Rev. 2000, 100, 2407; (b) Saleem, M.; Kim, H. J.;
Ali, M. S.; Lee, Y. S. Nat. Prod. Rep. 2005, 22, 696; (c) Whiting, D. A. Nat. Prod. Rep.
1990, 7, 349; (d) Whiting, D. A. Nat. Prod. Rep. 1985, 2, 191; (e) Whiting, D. A.
Nat. Prod. Rep. 1987, 4, 499; (f) Ward, R. S. Nat. Prod. Rep. 1995, 12, 183; (g)
MacRae, W. D.; Tower, G. H. N. Phytochemistry 1984, 23, 1207; (h) Ayres, D. C.;
Loike, J. D. In Lignans: Chemical, Biological and Clinical Properties; Cambridge
University Press: Cambridge, 1990; (i) Kang, E. J.; Lee, E. Chem. Rev. 2005, 105,
4348; (j) Goering, B. K. Ph.D. Dissertation, Cornell University, 1995.
CHCl3). IR (neat) vmax; 3019, 2920, 2401, 1783, 1689, 1613, 1516, 1382, 1386,
1215, 1030, 928, 757, 668 cmꢀ1 1H NMR (400 MHz, CDCl3) 7.35 (d, J = 8.53 Hz,
.
2H), 7.21–7.25 (m, 3H), 6.99–7.02 (m, 2H), 6.88 (d, J = 8.78 Hz, 2H), 5.06 (d,
J = 9.03 Hz, 1H), 4.78–4.85 (m, 3H), 4.63–4.69 (m, 1H), 4.25 (t, J = 8.79 Hz, 1H),
4.00–4.09 (m, 3H), 3.80 (s, 3H), 3.54 (dd, J = 9.04, 16.82 Hz, 1H), 3.11 (dd,
J = 3.27, 13.56 Hz, 1H), 2.53 (dd, J = 9.29, 13.30 Hz, 1H), 1.82 (s, 3H). 13C NMR
(100 MHz, CDCl3), 172.8, 159.7, 152.5, 142.9, 134.8, 130.6, 129.3, 128.9, 128.1,

2978
G. Pandey et al. / Tetrahedron Letters 51 (2010) 2975–2978
127.3, 113.9, 113.1, 86.2, 71.8, 65.5, 55.2, 54.2, 53.1, 37.7, 19.0. Mass (ESI-MS);
17. CCDC number for compound 9c is 736220.
18. Yu, H.-J.; Chen, C.-C.; Shih, B.-J. J. Nat. Prod. 1998, 61, 1017.
19. Nakato, T.; Yamauchi, S. J. Nat. Prod. 2007, 70, 1588.
m/z 444.38 (M+Na)+, 460.35 (M+K)+. Anal. Calcd for C25H27NO5: C, 71.24; H,
6.46; N, 3.32; O, 18.98. Found: C, 71.20; H, 6.32; N, 3.28.