The stereoselective total synthesis of (+)-garvensintriol

Article abstract of DOI:10.1016/j.tetlet.2010.07.158

A simple and highly efficient stereoselective total synthesis of (+)-garvensintriol, isolated from the stem bark of Goniothalamus arvensis, is described using Sharpless kinetic resolution, MacMillan α-hydroxylation, and Horner-Wadsworth-Emmons olefination

Full text of DOI:10.1016/j.tetlet.2010.07.158

Tetrahedron Letters 51 (2010) 5529–5531
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The stereoselective total synthesis of (+)-garvensintriol
*
J. S. Yadav , U. V. Subba Reddy, B. Anusha, 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:
A simple and highly efficient stereoselective total synthesis of (+)-garvensintriol, isolated from the stem
Received 26 May 2010
Revised 24 July 2010
Accepted 27 July 2010
Available online 2 August 2010
bark of Goniothalamus arvensis, is described using Sharpless kinetic resolution, MacMillan
ation, and Horner–Wadsworth–Emmons olefination as the key steps.
a-hydroxyl-
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Sharpless kinetic resolution
Stereoselective epoxide opening
MacMillan a-hydroxylation
Horner–Wadsworth–Emmons reaction
Styryl lactones
The trees of genus Goniothalamus of the plant family Annona-
ceae have attracted considerable interest as a source of potent bio-
logically active styryllactones.1,2 Due to their proven use in folk
medicine in Taiwan, Malaysia, and India to treat rheumatism, ede-
ma, and as abortifacients and mosquito repellents, there has been
interest in the active ingredients as potential therapeutic targets.3
Styryl lactones are natural heterocyclic compounds with potential
cytotoxicity including antitumor, antifungal, and antibiotic proper-
ties.4 The novel styryl-pyrones, (+)-garvensintriol 1, (+)-etharven-
diol 3, were isolated from the stem bark of Goniothulamus
arvensis.5 Especially, isolated lactones can mainly be classified into
two groups related to the size of the lactone ring. The first group
consists of the six-membered lactones such as (+)-garvensintriol
1, (+)-goniotriol 2, and (+)-etharvendiol 3; the second group con-
sists of the five-membered lactone moiety, for example, (+)-cardio-
butanolide 4 and goniofufurone 5 as shown in Figure 1. Their
unique and intriguing structures coupled with diverse and useful
characteristics as well as their broad spectrum of activity have
made them attractive targets for total synthesis.6 Consequently,
we have recently reported the total synthesis of (+)-garvensintri-
ol.7a Due to the unusual structure and biological significance of this
class of compounds, we were encouraged to continue our program
on the total synthesis of bioactive lactones.7b–h
Horner–Wadsworth–Emmons olefination, and finally, the acid-cat-
alyzed cyclization.
Retrosynthetic analysis of 1 revealed that a key intermediate 14
can be synthesized through MacMillan
a-hydroxylation followed
by Horner–Wadsworth–Emmons olefination of the aldehyde de-
rived from the Swern oxidation of 12. The alcohol 12 could in turn
be obtained by opening of epoxy alcohol 9 with dry acetone. This
epoxy alcohol can be prepared from homopropargylic alcohol by
means of Chan alkyne reduction and Sharpless kinetic resolution
(Scheme 1).
Our synthetic approach began with the protection of homoprop-
argyl alcohol as its benzyl ether 6 by treating with NaH and benzyl
bromide. It was then treated with n-BuLi in THF to generate the lith-
ium acetylide, which was subsequently reacted with benzaldehyde
to give the propargyl alcohol 7. Compound 7 was reduced with
LiAlH4 in THF to afford the allyl alcohol 8.8 The key epoxy alcohol 9
was obtained in 45% yield with 96% ee by the Sharpless kinetic res-
olution9 of 8 using
L(+)-DET and TBHP. Then compound9 was treated
with dry acetone in the presence of BF3ꢀEt2O at 0 °C to furnish aceto-
nide 10 in 90% yield. This resulted in fixing of the two hydroxyl
groups as we reported earlier.10 Thereafter, alcohol 10 was protected
as its MOM ether 11 in 92% yield using Hunig’s base and MOMCl in
dry dichloromethane. Debenzylation of ether 11 with 10% Pd–C/H2
gave primary alcohol 12, which was then subjected to Swern oxida-
Herein, we report
a concise and flexible stereoselective
synthetic route for the total synthesis of (+)-garvensintriol 1 start-
ing from the readily available homopropargyl alcohol by employ-
tion to give aldehyde 13. Treatment of aldehyde 13 with
and nitrosobenzene gave an intermediate -oxyamino aldehyde
with high levels of enantioselectivity11,12 by means of
-oxidation.
L-proline
a
ing Sharpless kinetic resolution, MacMillan
a-hydroxylation,
a
Olefination of aminoxy aldehyde under Horner–Wadsworth–Em-
mons conditions followed by cleavage of the aminoxy bond gave
the
xyl group of compound 14 was treated with MOMCl in the presence
c-hydroxy-a
,b-unsaturated ester 14.13 The resulting free hydro-
* 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 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.158

5530
J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 5529–5531
4
OEt
OH
OH
OH
OH
OH
3
5
2
6
7
8
O
O
O
O
O
O
OH
OH
OH
1
(+)-Garvensintriol
[ 5S, 6R, 7S, 8S ]
(+)-Etharvendiol 3
(+)-Goniotriol
2
OH
OH OH OH
O
O
O
O
OH
OH
O
(+)-Goniofufurone
5
(+)-Cardiobutanolide
4
Figure 1. Examples of some lactone-containing natural products.
O
O
MOMO
MOMO
O
OH
O
CO2Et
OH
O
OH
O
OH OH
1
14
(+)- Garvensintriol
12
OH
HO
OBn
O
9
Scheme 1. Retrosynthetic analysis of (+)-garvensintriol 1.
OH
a
b
c
OBn
OH
OBn
7
6
OH O
OH
OH
d
e
OBn
OBn
OBn
O
O
9
8
10
O
MOMO
MOMO
O
g
f
OBn
h
OH
O
O
11
12
O
MOMO
MOMO
O
MOMO
O
CO2Et
CO2Et
j
i
O
O
O
OH
O
OMOM
14
15
13
O
MOMO
O
OH
O
CO2Et
k
l
O
OMOM
OH
OH
16
(+)- Garvensintriol
1
Scheme 2. Reagents and conditions: (a) (i) NaH, THF, 0–25 °C, 0.5 h; (ii) BnBr, 0–25 °C, 3 h, 90%; (b) n-BuLi, dry THF, ꢁ78 °C, PhCHO, 4 h , 85%; (c) LiAlH4, dry THF, reflux, 3 h,
95%; (d) (+)-diisopropyl-
L
-tartrate, TBHP, Ti(OiPr)4, dry DCM, ꢁ20 °C, 12 h, 45%; (e) BF3ꢀOEt2, dry acetone, 0 °C, 4 h, 90%; (f) MOMCl, DIPEA, dry DCM, 0 °C to rt, 6 h; 92%; (g)
10% Pd/C, H2, EtOAc, rt, 10 h, 92%; (h) Oxalyl chloride, dry DMSO, dry DCM, ꢁ78 °C, Et3N, 1 h 85%; (i) nitrosobenzene (1.0 equiv), L-proline (0.4 equiv), DMSO, 20 °C, 25 min,
then triethylphosphonoacetate, DBU, LiCl, 0 °C, 15 min, then MeOH, NH4Cl, Cu(OAc)2, rt, 24 h, 45% (one-pot); (j) MOMCl, DIPEA, dry DCM, 0 °C to rt, 6 h; 90%; (k) 10% Pd/C, H2,
EtOAc, rt, 10 h, 95%; (l) PTSA, MeOH, reflux, 1 h, 75%.

J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 5529–5531
5531
(c) Yadav, J. S.; Premalatha, K.; Harshavardhan, S. J.; Subba Reddy, B. V.
Tetrahedron Lett. 2008, 49, 6765; (d) Yadav, J. S.; Krishnam Raju, A.;
Purushothama Rao, P.; Rajaiah, G. Tetrahedron: Asymmetry 2005, 16, 328; (e)
Yadav, J. S.; Rao, B. M.; Rao, K. S.; Reddy, B. V. S. Synlett 2008, 1039; (f) Yadav, J.
S.; Reddy, P. M. K.; Reddy, P. V. Tetrahedron Lett. 2007, 46, 1037; (g) Yadav, J. S.;
Rao, K. V.; Prasad, A. R. Tetrahedron Lett. 2006, 47, 3773; (h) Yadav, J. S.; Srinivas,
R.; Sathaiah, K. Tetrahedron Lett. 2006, 47, 1603.
of base to afford MOM ether 15. Then compound 15 was subjected to
hydrogenation with Pd–C/H2 to provide compound 16 in good yield.
Deprotection of acetonide and MOM groups with concomitant cycli-
zation was achieved using p-TSA in refluxing methanol7c to afford
the target lactone, (+)-garvensintriol 1 in 75% yield from compound
16 as a yellowish oil (Scheme 2). The analytical and spectral proper-
ties of compound 1 were in good agreement with the data reported
in the literature.14
In conclusion, we have developed a stereoselective synthetic
route for the total synthesis of garvensintriol from readily available
homopropargyl alcohol. The salient features of this synthesis in-
clude the use of Sharpless kinetic resolution to yield epoxy alcohol,
8. (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.
9. Sharpless, K. B.; Katsuki, T. J. Am. Chem. Soc. 1980, 102, 5974.
10. (a) Yadav, J. S.; Rami Reddy, N.; Harikrishna, V.; Subba Reddy, B. V. Tetrahedron
Lett. 2009, 50, 1318; (b) Yadav, J. S.; Pratap, T. V.; Rajender, V. J. Org. Chem.
2007, 72, 5882.
11. Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am Chem. Soc. 2003,
125, 10808.
12. For other reports on proline-catalyzed oxidation of aldehydes see: (a)
Chandrasekhar, S.; Mahipal, B.; Kavitha, M. J. Org. Chem. 2009, 74, 9531; (b)
Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247; (c) Hayashi, Y.; Yamaguchi, J.;
Hibino, K.; Shoji, M. Tetrahedron Lett. 2003, 44, 8293; (d) Chandrasekhar, S.;
Yaragorla, S. R.; Sreelakhmi, L. Tetrahedron Lett. 2007, 48, 7339; (e) Zhong, G.
Chem. Commun. 2004, 606.
MacMillan
of key intermediate, that is,
a
-hydroxylation and HWE reaction for the construction
-hydroxy- ,b-unsaturated ester in a
c
a
single step, which allows the preparation of target molecule in a
short and efficient route.
13. (a) Yadav, J. S.; Reddy, U. V. S.; Reddy, B. V. S. Tetrahedron Lett. 2009, 50, 5984;
(b) Zhong, G.; Yu, Y. Org. Lett. 2004, 6, 1637; (c) Mangion, I. K.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2005, 127, 3697; (d) Varseev, G. N.; Maier, M. E. Org. Lett.
2007, 9, 1461.
Acknowledgment
14. Spectral data for compound 14: Pale yellow oily liquid, ½a D25
ꢂ
+11.5 (c 0.5,
U.V.S.R. thanks UGC, New Delhi, for the award of a fellowship.
References and notes
CHCl3), IR (neat): m ;
max 3451, 2924, 2854, 1714, 1660, 1158, 1032, 757 cmꢁ1 1H
NMR (CDCl3, 300 MHz): d 7.43–7.28 (m, 5H), 6.95 (dd, J = 15.8, 3.7 Hz, 1H), 6.13
(dd, J = 15.8, 2.2 Hz, 1H), 4.60 (d, J = 9.8 Hz, 1H), 4.23–4.13 (m, 4H), 3.86 (dd,
J = 9.0, 2.2 Hz, 1H), 3.81 (d, J = 6.0 Hz, 1H), 3.58 (t, J = 9.0 Hz, 1H), 3.10 (s, 3H),
1.58 (s, 3H), 1.47 (s, 3H), 1.32 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d
172.6, 147.7, 138.9, 129.6, 128.4, 127.7, 121.8, 99.4, 97.7, 75.8, 74.9, 74.7, 68.7,
60.2, 56.0, 29.2, 19.4, 14.3; ESI- MS: m/z: 381 (M+H)+, 398 (M+NH4)+, 403
(M+Na)+; HRMS (ESI) calcd for C20H28O7Na: 403.1732, found: 403.1735.
1. For a review on styryllactones from Goniothalamus species, see: Blazquez, M.
A.; Bermejo, A.; Zafra-Polo, M. C.; Cortes, D. Phytochem. Anal. 1999, 10, 161.
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; (c) Cave, A.; Figade‘re, B.; Laurens, A.; Cortes, D. Prog. Chem. Org.
Nat. Prod. 1997, 70, 81.
Compound 16: colorless liquid, ½a D25
ꢂ
+9.0 (c 0.5, CHCl3), IR (neat): mmax 2927,
1733, 1453, 1377, 1161, 1036, 760, 537 cmꢁ1
;
1H NMR (CDCl3, 500 MHz): d
3. For the cytotoxic activity and other bioactivity of styryllactones, see: (a)
Mereyala, H. B.; Joe, M. Curr. Med. Chem. Anti-Cancer Agents 2001, 1, 293; (b)
Wu, Y. C.; Duh, C. Y.; Chang, F. R.; Chang, G. Y.; Wang, S. K.; Chang, J. J.; McPhail,
D. R.; McPhail, A. T.; Lee, K. H. J. Nat. Prod. 1991, 54, 1077.
7.40–7.37 (m, 2H), 7.31–7.22 (m, 3H), 4.70 (dd, J = 2.4, 6.7 Hz, 2H), 4.55 (d,
J = 4.5 Hz, 1H), 4.15–4.04 (m, 3H), 3.91 (d, J = 5.7 Hz, 1H), 3.81 (m, 1H), 3.72 (d,
J = 9.6 Hz, 1H), 3.60 (dd, J = 1.9, 9.6 Hz, 1H), 3.35 (s, 3H), 2.98 (s, 3H), 2.44–2.32
(m, 2H), 2.06–1.91 (m, 2H), 1.51 (s, 3H), 1.45 (s, 3H), 1.20 (t, J = 7.7 Hz, 3H); 13
C
4. (a) Mu, Q.; Tang, W. D.; Liu, R. Y.; Li, C. M.; Lou, L. G.; Sun, H. D. Planta Med.
2003, 69, 826; (b) Pihie, A. H.; Stanslas, J.; Din, L. B. Anticancer Res. 1998, 18,
1739.
5. Bermejo, A.; Blazquez, M. A.; Sundar rao, K. Phytochemistry 1998, 47, 1375.
6. (a) Prasad, K. R.; Gholap, S. L. Synlett 2005, 2260; (b) Popsavin, V.; Grabez, S.;
Popsavin, M.; Krstic, I.; Kojic, V.; Bogdanovic, G.; Divjakovic, V. Tetrahedron Lett.
2004, 45, 9409; (c) Peris, E.; Cave, A.; Estornell, E.; Zafra-Polo, M. C.; Figadere,
B.; Cortes, D.; Bermejo, A. Tetrahedron 2002, 58, 1335; (d) Srikanth, G. S. C.;
Krishna, U. M.; Trivedi, G. K. Tetrahedron Lett. 2002, 43, 5471; (e) Harris, J. M.;
ODoherty, G. A. Tetrahedron 2001, 57, 5161.
NMR (CDCl3, 75 MHz): d 173.4, 139.5, 129.3, 128.5, 127.9, 99.0, 97.3, 97.2, 76.4,
75.6, 74.5, 74.0, 60.3, 55.9, 55.8, 30.5, 29.4, 26.7, 19.0, 14.2; ESI- MS: m/z: 449
(M+Na)+; HRMS (ESI) calcd for C22H34O8Na: 449.2151, found: 449.2141.
Compound 1: yellow oil liquid, ½a D25
ꢂ
+8.2 (c 0.3, EtOH), IR (neat): mmax 3410,
2924, 2854, 1753, 1649, 1455, 1194, 1080, 1024, 765, 705 cmꢁ1
;
1H NMR
(CDCl3, 300 MHz): d 7.46–7.35 (m, 5H), 4.94 (td, J = 7.5, 6.0, 2.2 Hz, 1H), 4.83 (d,
J = 6.7 Hz, 1H), 3.91 (dd, J = 8.3, 7.5 Hz, 1H), 3.60 (dd, J = 8.3, 2.2 Hz, 1H), 2.54–
2.21 (m, 4H); 13C NMR (CDCl3, 75 MHz): d 177.7, 136.8, 128.8, 128.7, 127.1,
79.4, 77.1, 75.0, 73.4, 29.7, 23.5; ESI-MS: m/z: 270 (M+NH4)+, 275 (M+Na)+;
HRMS (ESI) calcd for C13H16O5Na: 275.0895, found: 275.0898.
7. (a) Mohapatra, D. K.; Kumar, B. P.; Bhaskar, K.; Yadav, J. S. Synlett 2010, 1059;
(b) Yadav, J. S.; Rajaiah, G.; Krishnam Raju, A. Tetrahedron Lett. 2003, 44, 5831;