A simple and efficient synthesis of goniothalesdiol A

Article abstract of DOI:10.1016/j.tetasy.2012.05.002

A concise, simple, and efficient stereoselective total synthesis of goniothalesdiol A starting from commercially available 2-deoxy-d-ribose is described herein using a stereocontrolled Grignard reaction, olefin cross-metathesis, and oxy-Michael addition reactions as the key steps.

Full text of DOI:10.1016/j.tetasy.2012.05.002

Tetrahedron: Asymmetry 23 (2012) 659–661
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A simple and efficient synthesis of goniothalesdiol A
Pallavi Thakur a, Kumaraswamy Boyapelly a, , Raji Reddy Gurram a, Rakeshwar Bandichhor b,
⇑
⇑
,
Khagga Mukkanti c
a Maithili Life Sciences Pvt. Ltd, Plot No. 146 A, Phase-II, IDA, Mallapur, Hyderabad 500 076, India
b Innovation Plaza, IPD, R&D, Dr. Reddy’s Laboratories Ltd, Survey Nos. 42, 45, 46, and 54, Bachupally, Qutubullapur, R.R. District 500 073, Andhra Pradesh, India
c Institute of Science and Technology, Center for Environmental Science, JNT University, Kukatpally, Hyderabad 500 072, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise, simple, and efficient stereoselective total synthesis of goniothalesdiol A starting from commer-
Received 26 March 2012
Accepted 3 May 2012
Available online 8 June 2012
cially available 2-deoxy-
cross-metathesis, and oxy-Michael addition reactions as the key steps.
Ó 2012 Elsevier Ltd. All rights reserved.
D-ribose is described herein using a stereocontrolled Grignard reaction, olefin
1. Introduction
chael addition which can be manipulated further by acetonide
deprotection to give the target compound goniothalesdiol A. Ester
3 can in turn be obtained by olefin cross-metathesis of 4 with
methyl acrylate. Olefinic alcohol 4 was synthesized from commer-
In recent years, the synthesis of substituted tetrahydropyrans
has gained significant interest due to their potent biological proper-
ties. Tetrahydropyrans containing substituents at the 2- and 6-posi-
tions on the ring are observed in a large number of biologically
important natural products. A few examples which come under this
class include phorboxazole,1a ratjadone,1b lasnolide,1c leucascan-
drolide,1d scytoohycins,1e soranicin-A,1f swinholides,1g laulima-
lide,1h and zamponolide.1i The two major types of bioactive
compounds styryl lactones2 and acetogenins3 can be isolated from
Goniothalamus species belonging to the annonaceae family. Re-
cently goniothalesdiol A 1 and goniothalesacetate 2 (Fig. 1) were
isolated from the stems of a southern Taiwan tree Goniothalamus
amuyon. Goniothalesdiol A has been shown to possess a 2,3,4,6-tet-
rasubstituted pyran ring. The structure and relative configuration of
1 were determined on the basis of NMR spectroscopy and the abso-
lute configuration was predicted by biosynthesis.4 Previously five
syntheses have been reported, one based on a Sharpless kinetic res-
olution; the second synthesis based on a cross metathesis using
Grubb’s second generation catalyst; a third involves a chiron ap-
proach; the fourth is based on a Prins cyclization and last one is
using tandem aminoxylation–allylation reaction.5 Among those,
She et al. achieved the asymmetric total synthesis of goniothalesdiol
A in six steps with an overall yield of 30%.5 We have achieved a con-
cise, simple, and efficient total synthesis of goniothalesdiol A in six
steps and with 31% overall yield.
cially available 2-deoxy-D-ribose involving a chiral pool approach
using selective acetonide protection, one carbon homologation by
a Wittig reaction and stereocontrolled Grignard reaction with phe-
nyl magnesium bromide (Scheme 1).
2. Results and discussion
Initially, the synthesis began with the isopropylidine formation
at the secondary hydroxyl groups at C3 and C4 of 2-deoxy-D-ribose
6 with 2,2-dimethoxy propane in the presence of a catalytic
amount of PTSA to give compound 5.6 One carbon homologation
using a Wittig protocol on lactol 5 with methyltriphenylphospho-
nium iodide in the presence of KHMDS yielded olefenic alcohol 7.7
The primary alcohol in the resultant product 7 was oxidized to the
aldehyde by a Swern oxidation and the crude aldehyde was used
directly for the Grignard reaction with phenyl magnesium bromide
in dry ether at ꢀ78 °C. The required anti-alcohol 4 was obtained as
the major diastereomer in 63% yield after column chromatogra-
phy.8 The olefenic cross-metathesis reaction of 4 with methyl acry-
late employing Grubbs’ 2nd generation catalyst gave the desired
conjugated ester 3 as the exclusive product in 97% yield.9 The
key intermediate 3 has the required carbon chain with the appro-
priate stereochemistry. One pot cyclization and deprotection of 3
using p-TSA in benzene produced the tetrahydropyran moiety
and the acetonide group was subsequently removed by the addi-
tion of a protic solvent (methanol) to give the desired target mol-
ecule goniothalesdiol A 1 in 86% (Scheme 2).10 The authenticity
of synthetic goniothalesdiol A was confirmed by comparison of
all of the spectroscopic data and the specific rotation with that of
the natural product.4,5
According to our retro-synthetic analysis, the construction of
the tetrahydropyran ring of goniothalesdiol A would arise from
the key intermediate hydroxyl ester 3 by intramolecular oxy-Mi-
⇑
Corresponding authors. Tel.: +91 40 27150243; fax: +91 40 40062330 (K.B.).
E-mail addresses: kumarboyapally@gmail.com (K. Boyapelly), rakeshwarb@
drreddys.com (R. Bandichhor).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.05.002

660
P. Thakur et al. / Tetrahedron: Asymmetry 23 (2012) 659–661
benzophenone prior to use. All reactions were monitored by TLC
(silica-coated plates and visualized under UV light). Yields refer
to isolated yields. Air-sensitive reagents were transferred by a syr-
inge or a double-ended needle. 1H and 13C NMR spectra were re-
corded in CDCl3 solution on Brucker Avance 300 spectrometers.
Chemical shifts are reported relative to TMS as an internal stan-
dard. Column chromatography was performed on silica gel (60–
120 mesh) supplied by Acme Chemical Co., India. TLC was per-
formed on Merck 60 F-254 silica gel plates. IR (FT-IR) spectra were
recorded either on KBr pellets or neat as thin film. Optical rotations
were recorded on JASCO DIP-360 digital polarimeter.
OMe
O
O
H
H
CO2Me
O
OMe
HO
OH
HO
OCOCH3
goniothalesdiol A 1
gonthalesacetate 2
Figure 1.
4.1.1. (2R,3S)-Hex-5-ene-1,2,3-triol 2,3-acetonide 7
To a stirred suspension of methyltriphenylphosphonium iodide
(13.9 g, 34.5 mmol) in 50 mL of THF was added KHMDS (0.5 M in
toluene, 57.5 mL, 28.7 mmol) at ꢀ78 °C. The solution was warmed
up to 0 °C and stirred for 30 min before being cooled down to
ꢀ78 °C. Compound 5 (2 g, 11.5 mmol) in 10 mL of THF was added
and the solution was stirred at rt overnight (10 h) before being
quenched with a saturated aqueous NH4Cl solution and extracted
with EtOAC (120 mL ꢁ 3). The organic layers were combined and
dried over anhydrous MgSO4, filtered, and concentrated under re-
duced pressure. The residue was purified on a silica gel column
using petroleum ether/EtOAc (4/1) as the eluant to afford 7 as a
colorless oil (1.30 g, 66%). Rf = 0.2 (SiO2, 3:7 EtOAc in hexane).
O
O
O
OH
O
HO
O
O
OH
O
3
goniothalesdiol A 1
O
OH
O
Ph
O
O
HO
O
4
5
½
a 2D9
ꢂ
¼ þ54:8 (c 1.2, CHCl3); IR (neat)
mmax: 3434, 2986, 2934,
2879, 1642, 1371, 1381, 1218 cmꢀ1 1H NMR (400 MHz, CDCl3): d
.
Scheme 1.
5.90–5.78 (m, 1H), 5.19–5.09 (m, 2H), 4.29–4.23 (m, 1H), 4.18 (q,
J = 7.3 Hz, 1H), 3.65 (d, J = 5.7 Hz, 2H), 2.46–2.36 (m, 1H), 2.33–
2.24 (m, 1H), 1.49 (s, 3H), 1.38 (s, 3H); 13CNMR (100 MHz, CDCl3);
d 134.2, 117.4, 108.2, 77.2, 76.2, 61.6, 33.6, 28.1, 25.4.
3. Conclusion
In conclusion, we have achieved a simple, versatile, and efficient
stereoselective total synthesis of goniothalesdiol A in six steps with
31% overall yield starting from the 2-deoxy-D-ribose. The key reac-
tions involved are the stereocontrolled Grignard reaction, olefin
cross-metathesis, and acid-catalyzed oxy-Michael addition.
4.1.2. (R)-[(4R,5S)-5-Allyl-2,2-dimethyl-1,3-dioxolan-4-yl](phe-
nyl)methanol 4
A solution of DMSO (1.65 mL, 23.2 mmol) in CH2Cl2 (10 mL) was
added to a solution of (COCl)2 (1.0 mL, 22.9 mmol) in CH2Cl2
(10 mL) at ꢀ78 °C. After stirring for 15 min, a solution of 7 (1.0 g,
5.8 mmol) in CH2Cl2 (20 mL) was added to the reaction mixture
and stirring was continued at the same temperature for an addi-
tional hour. Next, Et3N (4.8 mL, 34.8 mmol) was added to the reac-
tion mixture, which was then gradually warmed to rt and diluted
with CH2Cl2 (20 mL). The organic layer was washed with water
(1 ꢁ 30 mL), brine (1 ꢁ 20 mL), dried over anhydrous Na2SO4, and
4. Experimental
4.1. General
The reactions were carried out under N2 in anhydrous solvents
such as CH2Cl2, THF, and EtOAc. THF used was freshly distilled over
O
OH
O
OH
O
2,2-dimethoxy
propane
KHMDS, Ph3P+CH3I-
HO
PTSA, acetone,
12h, rt, 90%
THF, -78 °C-rt
66%
O
HO
O
O
OH
7
6
5
i) (COCl)2, DMSO,
TEA, DCM,1h,
-78 °C
O
O
Ph
Ph
+
ii) PhMgBr
Et2O, 6h, -78 °C
HO
O
HO
O
4 (63%)
4a (14%)
CO2Me
O
O
O
O
Grubbs catalyst
2nd generation
i) p-TSA, benzene
Ph
O
4
O
ii) methanol, 5h, 86%
DCM, rt, 3h, 97%.
HO
O
HO
3
OH
goniothalesdiol A 1
Scheme 2.

P. Thakur et al. / Tetrahedron: Asymmetry 23 (2012) 659–661
661
concentrated under reduced pressure. The crude aldehyde was
used directly for the next reaction.
for 3 h and the solvent was removed under reduced pressure, the
obtained crude residue was dissolved in 2 ml MeOH, and TsOH
(3.9 mg, 0.02 mmol) was added and stirred overnight at rt. The sol-
vent was removed under reduced pressure. The crude residue was
subjected to column chromatography on silica gel (hexane/AcOEt
6:4) to afford goniothalesdiol A (51 mg, 86%) as white solid. Mp
To a pre-cooled (ꢀ78 °C) stirred solution of the PhMgBr [pre-
pared from PhBr (1.2 mL, 11.6 mmol) and Mg (348 mg, 14.5 mmol)
in anhydrous ether (20 mL) at room temperature], the above pre-
pared aldehyde was added dropwise in anhydrous ether (10 mL),
and the resulting mixture was stirred at the same temperature
for 6 h. The reaction was quenched with an aqueous saturated
ammonium chloride solution (10 mL), and the reaction mixture
was diluted with Et2O (15 mL). The organic layer was washed with
NH4Cl (aq) (30 mL), and dried over anhydrous Na2SO4 which upon
evaporation of the solvent, yielded a mixture of diastereomers,
which were carefully separated by column chromatography 230–
400 silica gel (ethylacetate/hexane 1:9) to afford 4a (0.20 g, 14%),
followed by pure major diastereomer 4 (0.90 g, 63%) as a colorless
oil. Rf = 0.4 (20% EtOAc/hexane).
91 °C (lit.5a mp 92 °C);
½
a 2D8
ꢂ
¼ ꢀ25:5 (c 1.2, CHCl3); Lit.5a
½
a 2D5
ꢂ
¼ ꢀ27:2 (c 0.3, CHCl3); IR (neat): 3425, 2924, 2856, 1732,
1441, 1168. 1H NMR (400 MHz; CDCl3): d 7.42–7.29 (m, 5H), 4.54
(d, J = 9.52 Hz, 1H), 4.43–4.33 (m, 1H), 4.23–4.17 (m, 1H), 3.65 (s,
3H), 3.49 (d, J = 9.5 Hz, 1H), 2.60 (dd, J = 15.4, 7.3 Hz, 1H), 2.44
(dd, J = 14.6, 5.7 Hz, 1H), 2.12–2.04 (m, 1H), 1.81 (br s, 1H), 1.78–
1.69 (m, 1H) 1.53 (br s, 1H). 13C NMR (100 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.
HRMS (ESI): m/z [M+H]+ calcd for C14H19O5: 267.1232: found:
267.1224.
4.1.2.1. Analytical data for compound 4.
½
a 2D9
ꢂ
¼ ꢀ2:1 (c 0.3,
Acknowledgments
CHCl3); IR (KBr): 3448, 2933, 2984, 1641, 1454, 1380, 1219,
1058; 1H NMR (400 MHz; CDCl3): d 7.43–7.28 (m, 5H), 5.80–5.69
(m, 1H), 5.11–5.04 (m, 2H), 4.70 (d, J = 57 Hz, 1H), 4.35 (t,
J = 5.7 Hz, 1H), 4.21–4.15 (m, 1H), 2.85 (br s, 1H), 2.54–2.44 (m,
1H), 2.29–2.20 (m, 1H), 1.58 (s, 3H), 1.40 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 140.6, 134.5, 128.6, 128.1, 127.3, 117.2,
108.4, 80.7, 76.7, 72.1, 34.3, 27.7, 25.2.
We are thankful to Dr. Reddy’s Laboratories Ltd for support and
Maithili Life Sciences Pvt. Ltd for financial assistance.
References
1. (a) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117, 8126–8131; (b)
Schummer, D.; Gerth, K.; Reichenbach, H.; Hofle, G. Liebigs Ann. 1995, 685–688;
(c) Horton, P. A.; Koehn, F. E.; Longley, R. E.; McConnell, O. J. J. Am. Chem. Soc.
1994, 116, 6015–6016; (d) D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Pietra, F.
Helv. Chim. Acta 1996, 79, 51–60; (e) Moore, R. E.; Patterson, G. M. L.; Mynderse,
J. S.; Barchi, J., Jr. Pure Appl. Chem. 1986, 58, 263–271; (f) Ishibashi, M.; Moore, R.
E.; Patterson, G. M. L.; Xu, C.; Clardy, J. J. Org. Chem. 1986, 51, 5300–5306; (g)
Carmely, S.; Kashman, Y. Tetrahedron Lett. 1985, 26, 511–514; (h) Jansen, R.;
Wray, V.; Irschik, H.; Reichenbach, H.; Hofle, G. Tetrahedron Lett. 1985, 26,
6031–6034; (i) Tanaka, J.; Higa, T.; Kobayashi, M.; Kitagawa, I. Chem. Pharm.
Bull. 1990, 38, 2967–2970; (j) Tanaka, J.; Higa, T. Tetrahedron Lett. 1996, 37,
5535–5538;.
2. (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.
3. (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.
4.1.2.2. Analytical data for compound 4a.
½
a 2D9
ꢂ
¼ ꢀ8:5 (c 0.3,
CHCl3); IR (KBr): 3411, 2925, 2854, 1641, 1600, 1494, 1452, 916,
700; 1H NMR (400 MHz; CDCl3): d 7.56–7.01 (m, 5H), 6.04–5.86
(m, 1H), 5.09 (ddd J = 15.9, 11.0, 1.3 Hz, 2H), 4.56 (d, J = 9.3 Hz,
1H), 3.91–3.83 (m, 1H), 3.27 (t, J = 9.3, Hz, 1H), 2.60–2.50 (m,
1H), 2.36–2.25 (m, 1H), 1.59 (s, 3H), 1.49 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 143.7, 134.5, 128.4, 127.5, 126.5, 117.0,
108.4, 76.2, 72.8, 72.2, 36.8, 29.5, 19.4.
4.1.3. (E)-Methyl 4-{(4S,5R)-5-[(R)-hydroxy(phenyl)methyl]-2,2-
dimethyl-1,3-dioxolan-4-yl}but-2-enoate 3
Compound 4 (0.3 g, 1.2 mmol) and methyl acrylate (0.728 g,
8.5 mmol) were added via syringe to a stirring solution of Grubbs
2nd generation catalyst (50 mg, 0.05 mmol, 5.0 mol %) in dichloro-
methane (1.5 mL). The flask was capped with a rubber septum,
flushed with dry nitrogen, and stirred under nitrogen for 3 h at
rt. The reaction mixture was then reduced in volume to 0.5 mL
and purified directly by silica gel column chromatography (6%
EtOAc/hexane) to provide 3 (0.356 g, 97% yield) as a brown oil.
4. Lan, Y.-H.; Chang, F.-R.; Yang, Y.-L.; Wu, Y.-C. Chem. Pharm. Bull. 2006, 54, 1040–
1043.
5. (a) Yadav, J. S.; Rami Reddy, N.; Harikrishna, V.; Subba Reddy, B. V. Tetrahedron
Lett. 2009, 50, 1318–1320; (b) Yadav, J. S.; Nageshwar Rao, R.; Somaiah, R.;
Harikrishna, V.; Subba Reddy, B. V. Helv. Chim. Acta 2010, 93, 1362–1368; (c)
Venkataiah, M.; Somaiah, P.; Reddipalli, G.; Fadnavis, N. W. Tetrahedron:
Asymmetry. 2009, 20, 2230–2233; (d) Li, J.; Zheng, H.; Su, Y.; Xie, X.; She, X.
Synlett 2010, 2283–2284; (e) Sabitha, G.; Rammohan Reddy, T.; Yadav, J. S.
Tetrahedron Lett. 2011, 52, 6550–6553.
6. Jogireddy, R.; Dakas, P. Y.; Valot, G.; Barluenga, S.; Winssinger, N. Chem. Eur. J.
2009, 15, 11498–11506.
7. Geng, X.; Danishefsky, S. J. Org. Lett. 2004, 6, 413–416.
8. Kanger, T.; Niidas, P.; Müürisepp, A. M.; Pehk, T.; Lopp, M. Tetrahedron:
Asymmetry. 1998, 9, 2499–2508.
9. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360–11370.
10. Paterson, I.; Anderson, E. A.; Dalby, S. M.; Genovino, J.; Lim, J. H.; Moessner, C.
Chem. Commun. 2007, 1852–1854.
Rf = 0.40 (50% EtOAc in hexane). ½a D28
¼ ꢀ87:2 (c 0.15, CHCl3); IR
ꢂ
(KBr): 3451, 2935, 2987, 1722, 1658, 1437, 1219, 1059; 1H NMR
(400 MHz; CDCl3): d 7.41–7.30 (m, 5H), 6.92–6.83 (m, 1H), 5.84
(dt, J = 15.9, 1.3 Hz, 1H), 4.67 (dd, J = 4.4, 1.3 Hz, 1H), 4.41 (t,
J = 6.2 Hz, 1H), 4.23–4.17 (m, 1H), 3.71 (, 3H), 2.79 (d, 1H), 2.67–
2.57 (m, 1H), 2.38–2.29 (m, 1H), 1.57 (s, 3H), 1.39 (s, 3H); 13C
NMR (100 MHz, CDCl3): d 166.6, 144.9, 140.1, 128.7, 128.4, 127.3,
123.1, 108.7, 80.6, 75.7, 75.2, 51.5, 33.0, 27.7, 25.2; (ESI-MS): m/z
307 (M+H+). HRMS: calcd for C17H22NaO5: 329.1364 (M+Na),
found: 329.1372.
4.1.4. Goniothalesdiol A 1
To compound 3 (69 mg, 0.2 mmol) in benzene (2 ml) was added
TsOH (3.9 mg, 0.02 mmol). The reaction mixture was stirred at rt