First stereoselective total synthesis of (+)-dodoneine

Article abstract of DOI:10.1016/j.tetlet.2008.07.027

The first stereoselective total synthesis of the natural product (+)-dodoneine is described involving a Crimmins aldol reaction and a Horner-Wadsworth-Emmons olefination as the key steps.

Full text of DOI:10.1016/j.tetlet.2008.07.027

Tetrahedron Letters 49 (2008) 5590–5592
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Tetrahedron Letters
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First stereoselective total synthesis of (+)-dodoneine
*
P. Srihari , G. Rajendar, R. Srinivasa Rao, J. S. Yadav
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad, Andhra Pradesh 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The first stereoselective total synthesis of the natural product (+)-dodoneine is described involving a
Crimmins aldol reaction and a Horner–Wadsworth–Emmons olefination as the key steps.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 12 May 2008
Revised 25 June 2008
Accepted 3 July 2008
Available online 6 July 2008
a,b-Unsaturated
c
- and d-lactone motif-containing molecules
our interest in the total synthesis of biologically active a,b-unsatu-
continue to attract the attention of medicinal and organic chemists
due to their interesting biological properties.1 Our own interest in
the synthesis of biologically active molecules has led to the total
synthesis of several lactone-containing natural products and other
analogues.2 Recently, the dihydropyranone (R)-6-[(S)-2-hydroxy-
rated lactone-containing molecules, we chose to synthesize
dodoneine. Herein, we report the first total synthesis of (+)-
dodoneine.
Retrosynthetic analysis revealed an intermediate 2 which can
be synthesized by Horner–Wadsworth–Emmons olefination of
the aldehyde obtained by reaction of 3 with DIBAL-H. The two
asymmetric centre in compound 3 were realized from double
Crimmins aldol reaction starting from the aldehyde 5, which in
turn can be obtained from commercially available 4-hydroxybenz-
aldehyde (Scheme 1).
Thus, our synthesis started with 2C-Witting homologation of
4-hydroxybenzaldehyde 6 with (carboethoxymethylene)triphenyl-
phosphorane and protection of the resulting product with TBSCl to
yield TBS ether 7. The compound 7 was treated with LiAlH4 and
oxidized with PCC to afford aldehyde 5 in 86% overall yield. The
aldehyde 5 was treated with (S)-1-(4-benzyl-2-thioxothiazolidin-
3-yl)ethanone5 in the presence of titanium chloride using the
Crimmins protocol6 to give the easily separable diastereomers of
b-hydroxy amide (having the required stereochemistry for the
4-(4-hydroxyphenyl)butyl]-5,6-dihydropyran-2-one
1 was iso-
lated from the methanolic extract of a hemiplant parasite, Tapinan-
thus dodoneifolius DC Danser (known as African mistletoe) found on
a sheanut tree in Loumbila, West Africa.3 T. dodoneifolius is known
to be used as a remedy to treat cardiovascular and respiratory dis-
eases, and also for cholera, diarrhoea, stomach ache and wounds.4
The structure of the dihydropyranone 1 was determined from
spectroscopic and X-ray crystallographic analysis of the camphor-
sulfonate derivative of dodoneine. Compound 1 was found to exhi-
bit relaxation effects on preconstricted rat aortic rings with an IC50
value of 81.4 0.9 l
M.3 Even though, dodoneine can be extracted
in good amounts, to date there is no total synthesis of this mole-
cule. Intrigued by the therapeutic properties associated with T.
dodoneifolius, in particular by dodoneine, and in continuation of
O
OTBS OMOMO
S
OH
O
OTBS OMOM
N
S
COOMe
TBSO
HO
TBSO
3
Ph
2
1
OTBSO
S
CHO
N
O
S
HO
TBSO
TBSO
Ph
6
5
4
Scheme 1.
* Corresponding author. Tel.: +91 4027193002; fax: +91 4027160512.
E-mail addresses: srihari@iict.res.in, sriharipabbaraja@yahoo.com (P. Srihari).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.027

P. Srihari et al. / Tetrahedron Letters 49 (2008) 5590–5592
5591
1) Ph3PCHCO2Et
DCM, 12 h
CHO
1) LAH, THF
reflux, 30 min
COOEt
O
TBSO
2) PCC, DCM
0 oC-rt, 1 h
86%
2) TBSCl, imidazole
2 h, rt, 98%
HO
TBSO
5
6
7
O
S
N
S
OTBSO
OH
O
S
S
TBSCl,
2,6-lutidine
N
N
Ph
S
S
diastereomer
+
TiCl4, DIPEA
DCM, -78 o
85%
DMF, rt,
4 h, 98%
TBSO
TBSO
8 (syn
)
8a (anti
)
C
4
Ph
Ph
syn
72
O
:
:
anti
13
S
N
S
OTBSOH
O
OTBS
S
DIBAL-H
CHO
Ph
N
diastereomer
S
+
DCM, -78 oC,
5 min, 93%
TiCl4, DIPEA
DCM, -78 o
81%
TBSO
TBSO
9
C
10 (syn
)
10a (anti
)
Ph
syn
68
: anti
:
13
Scheme 2.
OTBSOMOM
CHO
OTBSOMOM O
S
MOMCl, DIPEA
DIBAL-H
DCM, -78 oC,
5 min, 93%
N
10
S
DCM, -78 o
76%
C
TBSO
TBSO
11
3
Ph
OTBSOMOM
(CF3CH2O)2P(O)CH2COOCH3
CO2CH3
NaH, THF, -78 oC,
82%
TBSO
2
Scheme 3.
O
O
O
H
OTBSOMOM
O
PTSA or
PPTS or
3 mol% HCl
OH
O
H
+
COOEt
H
HO
13
TBSO
HO
1
2
Scheme 4.
major syn product 8 along with the undesired minor anti product
8a (Scheme 2).7
and observed the formation of a significant amount of bicyclic
lactone 13 which was presumably due to the involvement of the
C7-hydroxyl group in the Michael addition reaction.9 However,
after careful investigation (see Table 1) with other acids such as
PPTS and 3 mol % HCl solution with respect to time and tempera-
ture, we found that 3 mol % HCl solution was the best in terms of
yield of the required target. The spectral properties of synthetic
target 110 were compared with the natural product and found to
be similar.
The hydroxyl group in 8 was protected to give TBS ether 4,
which was then treated with DIBAL-H to yield aldehyde 9 in 93%
yield. The aldehyde 9 was subjected to the Crimmins aldol reaction
with (S)-1-(4-benzyl-2-thioxothiazolidin-3-yl)ethanone following
the earlier protocol to afford the easily separable diastereomers
10 and 10a.
At this stage, based on the prior results of aldol reaction, we
proceeded further with the polar major 1,3-diol expecting it to
be the required 1,3-syn diol. The required geometry was also real-
ized at the later stage by comparing the synthesized target mole-
cule 1 with the natural product. The free hydroxyl group in
compound 10 was masked with MOMCl to yield MOM ether 3.
The amide 3 was treated with DIBAL-H to provide aldehyde 11
which was further subjected to a Horner–Wadsworth–Emmons
olefination reaction employing bis(2,2,2-trifluoromethyl)(methoxy
In conclusion, we have achieved the stereoselective total
synthesis of the natural product (+)-dodoneine
1 starting
from 4-hydroxybenzaldehyde employing a Horner–Wadsworth–
Table 1
Entry
Acid, solvent, conditions
Yieldb of 1 + 13 (%)
Ratio of 1:13
1
2
3
4
5
6
PTSA, MeOH, 12 h, rta
—
—
80
85
70
70
carbonylmethyl)phosphonate8 to give the cis-olefinic ester
2
PPTS, MeOH, 12 h, rta
(Scheme 3).
PTSA, MeOH, 1 h reflux
PPTS, MeOH, 2 h, reflux
3 M HCl, THF (1:1), 3 h, rt
3 M HCl, THF (1:1), 18 h, rt
25/75
30/70
70/30
20/80
With cis-olefinic ester 2 in hand, we proceeded further with the
one-pot global deprotection of the silyl and MOM groups and
simultaneous cyclization of the ester and alcohol functionalities
with an acid catalyst to give the target product 1 (Scheme 4). In
this end, we started with a catalytic amount of PTSA in methanol
a
Only TBS deprotection was observed even after 12 h.
Isolated combined yield.
b

5592
P. Srihari et al. / Tetrahedron Letters 49 (2008) 5590–5592
with the known syn and anti products whose structure was determined by X-
ray crystallographic analysis. See Ref. 6b.
8. Ando, K. J. Org. Chem. 1997, 62, 1934–1939.
9. The bicyclic lactone obtained was compared with the product obtained by
treatment of dodoneine with K2CO3 as reported in Ref. 3 and was found to be
identical.
Emmons olefination and Crimmins aldol approach as the key steps
to obtain the required stereochemistry of the target molecule in
twelve steps with an overall yield of 14.7%. Application of this
strategy to obtain other isomers for evaluation of their biological
properties is currently being investigated.
10. Spectral data for selected compounds: (S)-1-((S)-4-benzyl-2-thioxothiazolidin-
3-yl)-5-(4-tert-butyldimethylsilyloxy)phenyl)-3-hydroxypentan-1-one (8): Yellow
oil; ½a 2D5
ꢀ
+109.2 (c 0.60, CHCl3); IR (neat): 3400, 2929, 2856, 1688, 1607, 1508,
Acknowledgement
1463, 1258, 1163, 1138, 1040, 914, 839, 780, 746, 700 cmꢁ1
;
1H NMR
(300 MHz, CDCl3): d 0.18 (s, 6H), 0.97 (s, 9H), 1.70–1.91 (m, 2H), 2.60–2.80
(m, 3H), 2.84 (d, J = 11.3 Hz, 1H), 2.99–3.23 (m, 3H), 3.40 (dd, J = 12.0, 7.5 Hz,
1H), 3.66 (dd, J = 17.9, 2.3 Hz, 1H), 4.09–4.17 (br multiplet, 1H), 5.35–5.42 (m,
1H), 6.75 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 8.3 Hz, 2H), 7.26–7.37 (m, 5H); 13C NMR
(75 MHz, CDCl3): ꢁ4.4, 18.1, 25.6, 29.6, 30.9, 31.9, 36.8, 38.0, 40.2, 45.8, 67.1,
68.2, 119.9, 127.2, 128.9, 129.2, 129.4, 134.2, 136.3, 153.6, 173.1, 201.3. (R)-1-
((S)-4-Benzyl-2-thioxothiazolidin-3-yl)-5-(4-(tert-butyldimethylsilyloxy)phenyl)-
3-hydroxypentan-1-one (8a): 1H NMR (300 MHz, CDCl3): d 0.18 (s, 6H), 0.97 (s,
9H), 1.67–1.95 (m, 2H), 2.58–2.83 (m, 2H), 2.89 (d, J = 11.7 Hz, 1H), 3.03 (dd,
J = 14.2, 11.4 Hz, 1H), 3.21 (dd, J = 13.5, 2.4 Hz, 1H), 3.31 (dd, J = 17.4, 2.7 Hz,
1H), 3.39 (dd, J = 11.4, 7.4 Hz, 1H), 3.50 (dd, J = 17.7, 9.3 Hz, 1H), 3.98–4.11 (m,
1H), 5.34–5.43 (m, 1H), 6.74 (d, J = 8.6 Hz, 2H), 7.05 (d, J = 8.6 Hz, 2H), 7.23–
7.38 (m, 5H). 13C NMR (75 MHz, CDCl3): ꢁ4.2, 18.4, 25.9, 31.0, 32.3, 37.0, 38.5,
45.7, 67.8, 68.4, 120.1, 127.5, 129.1, 129.5, 129.6, 134.5, 136.5, 153.9, 173.9,
201.6. MS-ESIMS: m/z 538 (M+Na)+; HRMS calcd for C27H37NO3NaS2Si:
538.1889, found 538.1881. (3S,5S)-1-((S)-4-Benzyl-2-thioxothiazolidin-3-yl)-
5-(tert-butyldimethylsilyloxy)-7-(4-(tert-butyldimethylsilyloxy)phenyl)-3-hydr-
One of us (G.R.) thanks CSIR, New Delhi for financial assistance.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.07.027.
References and notes
1. (a) Hoffman, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1985, 24, 94–110; (b)
Negishi, E.; Kotora, M. Tetrahedron 1997, 53, 6707–6738; (c) Collins, I. J. Chem.
Soc., Perkin Trans. 1 1999, 1377–1395; (d) Alemany, A.; Marquez, C.; Pascual, C.;
Valverde, S.; Martinez-Ripoll, M.; Fayos, J.; Perales, A. Tetrahedron Lett. 1979, 20,
3583–3586.
2. (a) Srihari, P.; Kumar, B. P.; Subbarayudu, K.; Yadav, J. S. Tetrahedron Lett. 2007,
48, 6977–6981; (b) Srihari, P.; Ravindar, K.; Somaiah, R.; Yadav, J. S. Synth.
Commun. 2008, 1389–1397; (c) Srihari, P.; Vijayabhaskar, E.; Harshavardhan, J.;
Yadav, J. S. Synthesis 2006, 4041–4045.
oxyheptan-1-one (10): Yellow semi-solid; ½a D25
ꢀ
+77.8 (c 0.80, CHCl3); IR (neat):
3435, 2926, 2855, 1683, 1609, 1508, 1258, 1164, 1041, 915, 839, 771,
699 cmꢁ1 1H NMR (300 MHz, CDCl3): d 0.07 (s, 6H), 0.18 (s, 6H), 0.90 (s,
;
9H), 0.97 (s, 9H), 1.68–1.90 (m, 4H), 2.58 (t, J = 9.0, 7.5 Hz, 2H), 2.88 (d,
J = 12.0 Hz, 1H), 3.04 (dd, J = 12.8, 9.8 Hz, 1H), 3.20-3.30 (m, 3H), 3.39 (dd,
J = 12.0, 7.5 Hz, 1H), 3.55 (dd, J = 17.3, 3.0 Hz, 1H), 3.98 (m, 1H), 4.27–4.40
(br multiplet, 1H), 5.35–5.46 (m, 1H), 6.75 (d, J = 8.3 Hz, 2H), 7.02 (d,
J = 8.3 Hz, 2H), 7.23–7.37 (m, 5H); 13C NMR (75 MHz, CDCl3): ꢁ4.2, ꢁ4.1,
ꢁ3.9, 1.2, 18.2, 18.4, 25.9, 26.1, 29.9, 30.6, 32.2, 37.0, 39.6,42.9, 46.4, 66.7,
68.5, 71.1, 120.1, 127.4, 129.1, 129.3, 129.6, 135.0, 136.6, 153.8, 172.7,
201.5; MS-ESIMS: m/z 674 (M+H)+; HRMS calcd for C35H56NO4S2Si2:
674.31897, found 674.31838. (+)-Dodoneine or (R)-6-((S)-2-hydroxy-4-(4-
hydroxyphenyl)butyl-5,6-dihydropyran-2-one (1): Colorless solid, mp 57–
3. Ouedragogo, M.; Carreyre, H.; Vandebrouck, C.; Bescond, J.; Raymond, G.;
Guissou, I.-P.; Cognard, C.; Becq, F.; Potreau, D.; Cousson, A.; Marrot, J.;
Coustard, J.-M. J. Nat. Prod. 2007, 70, 2006–2009.
4. The chemical screening of T. dodoneifolius also indicated the presence of other
functional skeletons such as alkaloids, anthraquinones, terpenes and sterols.
See (a) Cepleanu, F.; Hamburger, M. O.; Sordat, B.; Msonthi, J. D.; Gupta, M. P.;
Saadou, M.; Hostettman, K. Int. J. Pharmacol. 1994, 323, 294–307; (b) Deeni, Y.
Y.; Sadiq, N. M. J. Ethnopharmacol. 2002, 83, 235–240; (c) Ouedraogo, S.; Traoré,
A.; Somé, N.; Lompo, M.; Guissou, P. I.; Schott, C.; Bucher, B.; Andriantsitohaina,
R. Afr. J. Trad. Comp. Alt. Med. 2005, 2, 25–30; (d) Ouedraogo, M.; Ouedraogo, S.;
Ouedraogo, L.; Traoré, A.; Belemtougri, G. R.; Sawadogo, L. L.; Guissou, I. P. Afr. J.
Trad. Comp. Alt. Mol. 2005, 2, 166–176.
5. For the synthesis of N-acetylthiazolidinethione complex see: Yadav, J. S.;
Naveen Kumar, V.; Srinivasa Rao, R.; Srihari, P. Synthesis 2008, 1938–1942.
6. (a) Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775. For the Crimmins
aldol approach see: (b) Hodge, M. B.; Olivo, H. F. Tetrahedron 2004, 60, 9397; (c)
Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem. 2001, 66,
894.
59 °C; ½a 2D5
ꢀ
+41.2 (c 0.35, CHCl3), Lit3 a 2D5
½ ꢀ +40.2 (c 0.4, CHCl3); IR (neat):
3417, 2924, 2853, 1715, 1607, 1511, 1461, 1381, 1257, 1217, 915, 837,
760 cmꢁ1 1H NMR (300 MHz, CDCl3): d 1.70–1.85 (m, 4H), 1.97–2.07 (m,
;
1H), 2.33–2.42 (br multiplet, 3H), 2.59–2.77 (m, 2H), 3.83–3.93 (br multiplet,
1H), 4.65 (dddd, J = 7.7, 7.7, 7.7, 5.3 Hz, 1H), 5.62-5.80 (br s, 1H, OH), 6.04
(dt, J = 9.8, 1.7 Hz, 1H), 6.78 (dt, J = 8.4, 2.6 Hz, 2H), 6.91 (dt, J = 9.6, 4.5 Hz,
1H), 7.06 (d, J = 8.3 Hz, 2H); 13C NMR (75 MHz, CDCl3): 29.6, 31.0, 39.5, 42.2,
68.8, 77.4, 115.5, 121.3, 129.6, 133.6, 145.7, 154.2, 164.5; MS-ESIMS: m/z
285 (M+Na)+; HRMS calcd for C15H18NaO4: 285.10986, found 285.10973.
Bicyclic lactone (13): White solid, mp 173–175 °C; ½a D25
ꢁ32.9 (c 0.50, CHCl3);
ꢀ
7. Based on the polarity difference, we expected the major isomer with high
IR (neat): 3338, 2924, 2856, 1685, 1517, 1451, 1382, 1347, 1230, 1076,
polarity to be the required syn product. This product
8
was further
1004, 821, 759 cmꢁ1 1H NMR (300 MHz, CDCl3): d 1.53–1.86 (m, 4H), 1.90–
;
characterized by 1H NMR chemical shift signals for the alpha-protons at
3.66 ppm (dd, J = 17.9, 2.3 Hz) for the less shielded proton and at 3.23 ppm (dd,
J = 17.9, 9.4 Hz, merged with thioxothiozolidine moiety) for the more shielded
proton. The anti product 8a gave chemical shift signals for the alpha-protons at
3.50 ppm (dd, J = 17.7, 9.3 Hz) for the less shielded proton and at 3.30 ppm (dd,
J = 17.7, 2.7 Hz) for the more shielded proton. These data were comparable
2.05 (m, 2H), 2.49–2.59 (m, 1H), 2.64–2.74 (m, 1H), 2.79–2.82 (m, 2H), 3.67–
3.76 (m, 1H), 4.38–4.43 (br multiplet, 1H), 4.88–4.93 (br multiplet, 1H),
5.21–5.52 (bs, 1H), 6.75 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.3 Hz, 2H); 13C NMR
(75 MHz, CDCl3): 29.9, 30.7, 36.5, 37.1, 38.0, 65.0, 66.0, 73.3, 115.5, 129.5,
133.6, 154.1, 170.3; MS-ESIMS: m/z 263 (M+H)+; HRMS calcd for C15H19O4:
263.12771, found 263.12779.