First stereoselective total synthesis of Goniothalesdiol A

Article abstract of DOI:10.1016/j.tetlet.2009.01.050

The first total synthesis of Goniothalesdiol A, isolated from the stems of Goniothalamus amuyon (Annonaceae) is reported. The C2 stereocentre and C3/C4 syn diol were created by a Sharpless kinetic resolution followed by acetonide formation. The tetrahydro

Full text of DOI:10.1016/j.tetlet.2009.01.050

Tetrahedron Letters 50 (2009) 1318–1320
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First stereoselective total synthesis of Goniothalesdiol A
*
J. S. Yadav , N. Rami Reddy, V. Harikrishna, B. V. Subba Reddy
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 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 total synthesis of Goniothalesdiol A, isolated from the stems of Goniothalamus amuyon (Annon-
aceae) is reported. The C2 stereocentre and C3/C4 syn diol were created by a Sharpless kinetic resolution
followed by acetonide formation. The tetrahydropyran ring was formed and the C6 stereocentre was fixed
by intramolecular oxy-Michael addition.
Received 26 November 2008
Revised 19 December 2008
Accepted 9 January 2009
Available online 15 January 2009
Ó 2009 Published by Elsevier Ltd.
Keywords:
Pyran
Stereoselective
Chan alkyne reduction
Sharpless kinetic resolution
Epoxide opening
Oxy-Michael addition
Natural products with 2,6-disubstituted tetrahydropyran scaf-
folds have gained prominence recently owing to their excellent
biological properties. Several natural products have the substituted
pyran moiety with cis stereoconnectivity at the 2,6-positions.1
Some recent examples, which fall into this class, include leucascan-
drolides,2 phorboxazoles,3 (+)-SCH 351448.4 The synthesis of these
compounds has attracted attention owing to their interesting bio-
logical properties and challenges posed by the substitution pattern.
The styryl lactones5 and acetogenins6 are two major types of
bioactive compounds isolated from the Goniothalamus (Annona-
ceae) species. Recently, two new compounds Goniothalesdiol A 1
and Goniothalesacetate 2 (Fig. 1) were isolated from the stems of
a southern Taiwan tree Goniothalamus amuyon. The structure and
relative stereochemistry of 1 were assigned on the basis of NMR
spectroscopy and the absolute configuration was predicted by
biosynthesis.7
O
OMe
H
H
H
H
O
4
OMe
O
7
6
8
2
3
6
5
2
5
OMe
7
3
4
O
O
H
HO
OCOCH3
OH
Goniothalesdiol A (1)
Goniothalesacetate (2)
Figure 1. Chemical structures of Goniothalesdiol A and Goniothalesacetate.
epoxy alcohol 7 was prepared by the Sharpless kinetic resolution10
of 6 using
D
(ꢀ)-DET and TBHP (80% yield, 96% ee).
Compound 7 was treated with anhydrous acetone in the pres-
ence of BF3ꢁEt2O at 0 °C to furnish acetonide 8 in 90% yield.11 This
resulted in the fixing of the two hydroxyl groups on C4 and C3 with
an axial–equatorial relationship in Goniothalesdiol A 1, which was
confirmed by 1H NMR analysis (J = 3.8 Hz).
In continuation of our interest in synthesising natural products
possessing a pyran moiety,8 we report herein an efficient synthetic
route to Goniothalesdiol A involving Chan alkyne reduction, Sharp-
less kinetic resolution and pyran ring formation by intramolecular
oxy-Michael addition as key steps (Scheme 1).
Alcohol 8 was protected as its TBDMS ether 9 by using
TBDMSCl and imidazole. The oxidative cleavage of ether 9 with
DDQ gave primary alcohol 10 which was subjected to Swern oxi-
dation to give the aldehyde which was treated with phosphorous
ylide in refluxing benzene to give the
a,b-unsaturated ester 11
Our synthesis began with the protection of homopropargyl
alcohol 3 as its benzyl ether 4 by treating with NaH and benzyl bro-
mide. The ether 4 was treated with n-BuLi in THF to generate the
lithium acetylide, which was subsequently reacted with benzalde-
hyde to give propargyl alcohol 5. Alcohol 5 was reduced with
LiAlH4 in THF to afford the allyl alcohol 6.9 The key intermediate
with trans-configuration. The TBDMS ether was deprotected by
treating with TBAF in dry THF at room temperature to give alcohol
12. Alcohol 12 was then treated with p-TSA in methanol at room
temperature to cleave the acetonide followed by intramolecular
oxy-Michael addition12 of the C2 hydroxyl group to the C6, C7
double bond to accomplish the target molecule Goniothalesdiol
A 1 (90%) (Scheme 2). The spectral data were identical in all re-
spects with that of the authentic sample.7,13 The C2, C6 syn stereo-
chemistry was achieved during the pyran ring formation and was
* Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.01.050

J. S. Yadav et al. / Tetrahedron Letters 50 (2009) 1318–1320
1319
OTBS
H
H
OH
O
COOMe
OBn
COOMe
O
HO
O
O
OH
7
11
1
OH
CHO
OBn
OH
+
6
3
3a
Scheme 1. Retrosynthetic analysis of Goniothalesdiol A.
OH
OH
a
OBn
b
c
OH
OBn
OBn
3
5
4
6
OH
HO
TBSO
O
O
e
d
OBn
g
f
OBn
O
OBn
O
O
7
8
9
TBSO
HO
O
TBSO
O
O
COOMe
k
COOMe
j
h, i
OH
1
O
O
O
10
12
11
Scheme 2. Reagents and conditions: (a) (i) NaH, DMF, 0–25 °C, 1 h, BnBr, 0–25 °C, 3 h 85%; (b) n-BuLi, dry THF, ꢀ78 °C, PhCHO, 4 h , 90%; (c) LiAlH4, dry THF, reflux, 3 h, 95%; (d)
(ꢀ)Diisopropyl-
D
-tartrate, TBHP, Ti (OiPr)4, dry DCM, ꢀ20 °C, 12 h, 80%; (e) BF3ꢁEt2O, dry acetone, 0 °C, 4 h, 88%; (f) TBDMSOTf, 2,6-lutidine, DCM, 0–25 °C, 1 h, 95%; (g) DDQ,
DCM, 25 °C, 2 h , 95%; (h) Oxalyl chloride, dry DMSO, dry DCM, ꢀ78 °C, Et3 N, quant.; (i) Ph3P@CHCOOMe, benzene, reflux, 1 h, 80%; (j) TBAF, dry THF, 25 °C, 2 h, quant.; (k)
PTSA, methanol, 25 °C, 2 h, 95%.
J= 3.8 Hz
References and notes
J= 2.7 Hz
1. (a) Galeffi, C.; Casinovi, C. G.; Marini-Bettolo, G. B. Gazz. Chim. Ital. 1965, 95–
100; (b) Aragao Craveiro, A.; daCosta Prado, A.; Gottlieb, O. R.; Welerson de
Albuquerque, P. C. Phytochemistry 1970, 9, 1869–1875; (c) Alcantara, A. F. deC.;
Souza, M. R.; Pilo-Veloso, D. Fitoterapia 2000, 71, 613–615.
J= 8.2 Hz
H
H
J= 13.8 Hz
H
OH
H
O
O
2. (a) Hornberger, K. R.; Hamblett, C. L.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122,
12894–12895; (b) Fettes, A.; Carreira, E. M. Angew. Chem., Int. Ed. 2002, 41,
4098–4101.
H3C
OH
H
H
O
J= 8.6 Hz
3. (a) Forsyth, C. J.; Ahmed, F.; Clink, R. D.; Lee, C. S. J. Am. Chem. Soc. 1998, 120,
5597–5598; (b) Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.; Schelhass, M. J.
Am. Chem. Soc. 2001, 123, 10942–10953.
Figure 2. Coupling correlations in 1H NMR spectroscopy.
4. (a) Soltani, O.; Brabander, J. K. D. Org. Lett. 2005, 13, 2791–2793; (b) Kang, E. J.;
Cho, E. J.; Lee, Y. E.; Ji, M. K.; Shin, D. M.; Chung, Y. K.; Lee, E. J. Am. Chem. Soc.
2004, 126, 2680–2681.
confirmed by measuring the coupling constants in 1H NMR spec-
troscopy of the final molecule Goniothalesdiol A 1.
5. (a) El-Zayat, A. A. E.; Ferringi, N. R.; McCloud, T. G.; McKenzie, A. T.; Byrn, S. R.;
Cassady, J. M.; Chang, C.-J.; McLaughlin, J. L. Tetrahedron Lett. 1987, 26, 955–
956; (b) Sam, T. W.; Chew, S. Y.; Matsjeh, S.; Gan, E. K.; Razak, D.; Mohamed, A.
L. Tetrahedron Lett. 1987, 28, 2541–2544; (c) Fang, X.-P.; Anderson, J. E.; Chang,
C.-J.; Fanwick, P. E.; McLaughlin, J. L. J. Chem. Soc., Perkin Trans. 1 1990, 1655–
1661; (d) Fang, X.-P.; Anderson, J. E.; Chang, C.-J.; Fanwick, P. E.; McLaughlin, J.
L. Tetrahedron 1991, 47, 9751–9758; (e) Fang, X.-P.; Anderson, J. E.; Qiu, X.-X.;
Kozlowski, J. F.; Chang, C.-J.; McLaughlin, J. L. Tetrahedron 1993, 49, 1563–1570.
6. (a) Gu, Z.-M.; Fang, X.-P.; Zeng, L.; McLaughlin, J. L. Tetrahedron Lett. 1994, 35,
5367–5368; (b) Fang, X.-P.; Anderson, J. E.; Smith, D. L.; Wood, K. V.;
McLaughlin, J. L. J. Nat. Prod. 1992, 55, 1655–1663.
7. Lan, Y.-H.; Chang, F.-R.; Yang, Y.-L.; Wu, Y.-C. Chem. Pharm. Bull. 2006, 54(7),
1040–1043.
8. (a) Yadav, J. S.; Nagalakshmi, P.; Harshavardan, S. J.; Subba Reddy, B. V. Synlett
2007, 12, 1945–1947; (b) Sabitha, G.; Reddy, K. B.; Kiran Kumar, R.; Narjis, F.;
Yadav, J. S. Synlett 2005, 2347–2351.
The stereochemistry of Goniothalesdiol A was assigned by anal-
ysis of 1H NMR coupling constants. The J 2/3 value 8.2 Hz indicated
the axial-axial position of H2 and H3. The observed J 5/6 value 8.6
Hz determined the confirmation of H6 as axial and J 3/4 Hz value
3.8 Hz indicated the axial–equatorial relationship between H3
and H4 (Fig. 2).
In conclusion, we have described a concise stereoselective syn-
thesis of Goniothalesdiol A in 11 steps from homopropargyl alcohol
in a highly stereoselective manner using Sharpless kinetic resolu-
tion and intramolecular oxy-Michael addition as key steps.
Acknowledgement
9. (a) Bates, E. V.; Jones, E. R. H.; Whiting, M. C. J. Chem. Soc. 1954, 1854; (b)
Eguchi, T.; Koudate, T.; Kakinuma, K. Tetrahedron 1993, 49, 4527.
10. Sharpless, K. B.; Katsuki, T. J. Am. Chem. Soc. 1980, 102, 5974–5976.
11. Yadav, J. S.; Pratap, T. V.; Rajender, V. J. Org. Chem. 2007, 72, 5882–5885.
N.R.R and V.H.K thank CSIR, New Delhi, for the award of
fellowships.

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J. S. Yadav et al. / Tetrahedron Letters 50 (2009) 1318–1320
12. Paterson, I.; Anderson, E. A.; Dalby, S. M.; Genovino, J.; Lim, J. H.; Moessner, C.
CHCl3). IR (neat):
m
2925, 2854, 1727, 1657, 1463, 1437, 1381, 1261, 1165,
1H NMR (300 MHz, CDCl3): d 8.37–8.20 (m, 5H), 8.0–
Chem. Commun. 2007, 1852–1854.
1095, 864, 836, 778 cmꢀ1
.
13. Spectroscopic data for compound (ꢀ)-7: ½a D25
ꢂ
ꢀ3.6 (c 1.5, CHCl3); IR (neat):
m
7.87 (m, 1H), 6.83 (d, J = 15.8 Hz, 1H), 5.43 (d, J = 9.0 Hz, 1H), 4.80–4.65 (m, 1H),
4.70 (s, 1H), 4.31 (t, J = 9.0 Hz, 1H), 3.70–3.60 (m, 1H), 3.28–3.15 (m, 1H), 2.54
(s, 3H), 2.34 (s, 3H), 1.73 (s, 9H), 0.84 (s, 3H), 0.30 (s, 3H). 13C NMR (75 MHz,
CDCl3): d 145.7, 128.7, 128.3, 122.7, 78.1 73.8, 73.1, 34.8, 29.4, 25.8, 19.4, ꢀ4.1,
ꢀ5.7. ESI-MS: m/z 443 (M+Na+); HRMS for C23H36O5NaSi: found: 443.2228,
calcd: 443.2229. Spectroscopic data for Goniothalesdiol A: White solid, mp 92 °C;
3425, 2923, 2855, 1491, 1452, 1361, 1098, 897, 739, 697 cmꢀ1
.
1H NMR (300
MHz, CDCl3): d 7.42–7.18 (m, 10H), 4.83 (s, 1H), 4.43 (s, 2H), 3.58–3.45 (m, 2H),
3.35–3.25 (m, 1H), 3.0–2.96 (m, 1H), 1.81 (dd, J = 5.4, 6.2 Hz, 2H). 13C NMR (50
MHz, CDCl3): d 139.6, 138, 128.2, 127.5, 126.4, 72.9, 71.0, 66.8, 61.0, 60.2, 53,
31.8. ESI-MS: m/z 307 (M+Na+); HRMS for C18H20O3Na: found: 307.1313, calcd:
307.1310. Spectroscopic data for compound (ꢀ)-8: Colourless liquid; ½a D25
ꢂ
ꢀ51.7
½ ꢂ ꢀ27.2 (c 0.3, CHCl3). IR (neat): m 3406, 2918, 2849, 2373, 1733, 1435, 1200,
a 2D5
(c 0.65, CHCl3); IR (neat):
m
3434, 2924, 2855, 1718, 1603, 1492, 1455, 1377,
1170, 1068 cmꢀ1; 1H NMR (300 MHz, CDCl3): d 7.40–7.28 (m, 5H), 4.54 (d,
J = 9.8 Hz, 1H), 4.45–4.35 (m, 1H), 4.24–4.19 (m, 1H), 3.68 (s, 3H), 3.49 (dd,
J = 9.8, 3.0 Hz, 1H), 2.61 (dd, J = 15.1, 7.5 Hz, 1H), 2.45 (dd, J = 15.1, 6.0 Hz, 1H),
2.11 (ddd, J = 13.5, 3.0, 2.2 Hz, 3H), 1.76 (ddd, J = 12.0, 3.0, 2.2 Hz, 3H), 1.40 (s,
1H); 13C NMR (75 MHz, CDCl3): d 171.3, 139.2, 128.4, 128.2, 127.3, 77.7, 72.6,
68.4, 67.0, 51.6, 40.3, 37.1; ESI-MS: m/z 267 (M+H+); HRMS for C14H19O5:
found: 267.1227, calcd: 267. 1232.
1205, 1074, 889, 755 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.42–7.23 (m, 10H),
;
4.58–4.55 (d, J = 3.0 Hz, 1H), 4.53 (s, 2H), 3.92–3.8 (m, 1H), 3.69–3.56 (m, 2H),
3.3–3.2 (t, J = 9.0 Hz, 1H), 2.95 (d, J = 2.2 Hz, 1H), 2.0–1.90 (m, 1H), 1.90–1.77
(m, 1H), 1.60 (s, 3H), 1.40 (s, 3H); 13C NMR (75 MHz, CDCl3): d 139.3, 137.5,
128.3, 127.7, 127.4, 127.1, 98.8, 73.0, 72.5, 66.6, 34.1, 29.6. ESI-MS: m/z 365
(M+Na+). HRMS for C21H26O4Na: found: 365.1726, calcd: 365.1728.
Spectroscopic data for compound (-)ꢀ11: Colourless liquid; ½a D25
ꢀ53.4 (c 0.3,
ꢂ