A concise enantioselective synthesis of (+)-goniodiol and (+)-8-methoxygoniodiol via Co-catalyzed HKR of anti-(2SR, 3RS)-3-methoxy-3- phenyl-1, 2-epoxypropane

Article abstract of DOI:10.1016/j.tetlet.2010.11.085

A short, enantioselective synthesis of (+)-goniodiol and (+)-8-methoxygoniodiol, cytotoxic styryllactones, has been achieved in high optical purities (99% ee). The strategy employs Co-catalyzed HKR of racemic anti-(2SR, 3RS)-3-methoxy-3-phenyl-1, 2-epoxypropane and Lewis acid-mediated diastereoselective allylation of aldehyde as chiral inducing key reactions.

Full text of DOI:10.1016/j.tetlet.2010.11.085

Tetrahedron Letters 52 (2011) 438–440
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Tetrahedron Letters
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A concise enantioselective synthesis of (+)-goniodiol and
(+)-8-methoxygoniodiol via Co-catalyzed HKR of anti-(2SR,
3RS)-3-methoxy-3-phenyl-1, 2-epoxypropane
⇑
I. N. Chaithanya Kiran, R. Santhosh Reddy, Gurunath Suryavanshi, Arumugam Sudalai
Chemical Engineering and Process Development Division, National Chemical Laboratory, Pashan 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:
A short, enantioselective synthesis of (+)-goniodiol and (+)-8-methoxygoniodiol, cytotoxic styryllactones,
has been achieved in high optical purities (99% ee). The strategy employs Co-catalyzed HKR of racemic
anti-(2SR, 3RS)-3-methoxy-3-phenyl-1, 2-epoxypropane and Lewis acid-mediated diastereoselective ally-
lation of aldehyde as chiral inducing key reactions.
Received 6 October 2010
Revised 15 November 2010
Accepted 16 November 2010
Available online 19 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Styryllactones
Racemic anti-epoxide
Hydrolytic kinetic resolution
Allylation
Diastereoselectivity
The genus Goniothalamus (Annonaceae) consists of over 115
species of shrubs and treelets growing abundantly in the rain for-
ests of tropical Asia.1 The extracts and leaves of Goniothalamus spe-
cies have traditionally been used as folk medicine: for example, in
the treatment of edema and rheumatism,2 abortifacient,3 labor
pain,4 etc. In particular, both (+)-goniodiol (1)4 and (+)-8-meth-
oxygoniodiol (2),5 which belong to styryllactone family, were iso-
first time, HKR of racemic anti-methoxy epoxide 6 (Scheme 1) and
demonstrated its effectiveness in the short enantioselective syn-
thesis of (+)-goniodiol (1) and (+)-8-methoxygoniodiol (2).
Firstly, the starting material anti-methoxy epoxide 6 was pre-
pared in three steps starting from commercially available cinnamyl
alcohol, which on epoxidation with mCPBA gave the epoxy alcohol
lated from Goniothalamus sesquipedalis and
Goniothalamus
amuyon, respectively. These bioactive natural products 1–5
(Fig.1) with relatively small and densely functionalised molecules
are found to exhibit significant cytotoxic activity6 including antitu-
mor and antifungal properties as well as antibiotic potential. Thus,
their unique structural features coupled with potent biological
activities make them ideal targets for testing new synthetic meth-
odology. Consequently, there have been important synthetic ef-
forts toward styryllactones 1–5 resulting in the number of their
total synthesis.7 However, some of the reported methods suffer
from certain limitations such as use of chiral building blocks and
exotic reagents, involvement of longer reaction sequence, etc. We
have recently reported a flexible, novel method that employs Co-
catalyzed HKR (Hydrolytic Kinetic Resolution) of racemic syn-alk-
oxy epoxides to generate the corresponding diols and epoxides
with two-stereocenters of high optical purity (97–98% ee) in a sin-
gle step.8a By applying the same strategy, we have achieved, for the
O
O
OR
O
OH
O
OH
OH
R = H; (+)-Goniodiol (1)
R = Me; (+)-8-Methoxygoniodiol (2)
(-)-6-epi-Goniodiol (3)
O
O
OH
O
OH
O
OH
(-)-8-epi-Goniodiol (5)
OH
(+)-7-epi-Goniodiol (4)
⇑
Corresponding author. Tel.: +91 20 25902174; fax: +91 20 25902676.
E-mail address: a.sudalai@ncl.res.in (A. Sudalai).
Figure 1. Structures of bioactive styryllactones.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.085

I. N. I. N. Chaithanya Kiran et al. / Tetrahedron Letters 52 (2011) 438–440
439
OMe
OMe
OMe
a
OH
+
O
O
OH
8 (2R, 3S)
yield = 48%; 96% ee
7 (2S, 3R)
anti-6 (2SR, 3RS)
yield = 47%; 98% ee
Scheme 1. Reagents and conditions: (a) (S,S)-Co(salen)OAc, (0.5 mol %), THF, H2O (0.5 equiv), 0 °C, 14 h.
OMe
OMe
O
c
b
a
OH
OH
OH
O
OH
anti-10
anti-6 (2SR, 3RS)
9
Scheme 2. Reagents and conditions: (a) mCPBA, CH2Cl2, 14 h, 0 °C, 88%; (b) camphor sulfonic acid (10 mol %), MeOH; 1 h, 96%; (c) (i) TsCl, Bu2SnO (2 mol %), Et3N, DMAP
(10 mol %), CH2Cl2, 2 h; (ii) K2CO3, MeOH, 3 h, 76% (two-steps).
9. The regiospecific opening of epoxide 9 with MeOH was achieved
quantitatively to give diol 10, which was further converted to race-
mic anti-methoxy epoxide 6 in a two-step reaction sequence: (i)
selective monotosylation of primary alcohol (TsCl, Bu2SnO, Et3N,
DMAP, CH2Cl2); (ii) formation of epoxide under basic conditions
(K2CO3, MeOH) (Scheme 2). Then, we became interested in subject-
ing anti-(2SR, 3RS)-3-methoxy-3-phenyl-1, 2-epoxypropane 6 to
HKR with (S,S)-salen Co(OAc) complex8a,b (0.5 mol %) and H2O
(0.5 equiv), which produced the corresponding chiral diol 716
(47%, 98% ee) and epoxide 8 (48%, 96% ee) in high optical purity
(Scheme 1). As compared to the reported methods, the present
strategy employs a truly catalytic amount of chiral cobalt-based
salen complex and water as the only reagent under mild conditions
that afforded diol 7 and epoxide 8, which are useful intermediates
in the asymmetric synthesis of other members of styryllactone
family. The chiral diol 7 was readily separated from epoxide 8 by
the column chromatographic purification and its primary hydroxyl
function selectively protected (TBSCl, imid., CH2Cl2, 25 °C)9 to ob-
tain the corresponding silyl ether 11 in 90% yield (Scheme 3). Pro-
tection of secondary alcohol in 11 as benzyl ether (BnBr, NaH, DMF,
25 °C)10 was then carried out to produce the protected ether 12 in
95% yield. The selective deprotection of TBS group was achieved
(TBAF, THF, 25 °C) to give back the primary alcohol 13 in 91% yield.
The smooth IBX oxidation of alcohol 13 at 25 °C gave the corre-
sponding crude aldehyde, which was found to be quite unstable
on exposure both to moisture as well as air. Hence, this crude alde-
hyde, was immediately subjected to Ti-mediated diastereoselec-
tive allylation (TiCl4, tri-n-butyl allyl stannane, CH2Cl2, ꢀ78 °C) to
furnish the key intermediate homoallylic alcohol 14 in 73% yield
over two-steps as a single diastereomer as determined from its
1H NMR spectrum of the crude product.11 Esterification of alcohol
14 with (E)-cinnamoyl chloride (py, DMAP, CH2Cl2, 25 °C) gave the
corresponding ester 15 in 64% yield.12 Ring closing metathesis of
the cinnamate ester 15 with Grubbs’ second generation catalyst
led to the isolation of a
-pyrone 16 in 76% yield.12 Finally, the oxi-
dative deprotection of benzyl group in 16 with DDQ was carried
OMe
OMe OH
OMe
OR'
d
a
OH
OR
OBn
OH
14
7
11 R = H; R' = TBS
12 R = Bn; R' = TBS
13 R = Bn; R' = H
b
c
O
O
OR
O
OMe
O
Ph
f
e
OR'
OBn
15
16 R = Me; R' = Bn
2 R = Me; R' = H
g
h
1 R = H; R' = H
Scheme 3. Reagents and conditions: (a) TBDMSCl, imidazole, CH2Cl2, 0–25 °C, 1 h, 90%; (b) NaH, DMF, BnBr, 0–25 °C, 2 h, 95%; (c) TBAF, THF, 25 °C, 8 h, 91%; (d) IBX, DMSO,
2 h, 25 °C then TiCl4, tributyl allyl stannane, CH2Cl2, ꢀ78 °C, 30 min, 73% (over two-steps); (e) (E)-cinnamoyl chloride, py, DMAP, CH2Cl2, 0–25 °C, overnight, 64%; (f) Grubbs’
second generation catalyst (10 mol %), CH2Cl2, reflux, 8 h, 76%; (g) DDQ, CH2Cl2/H2O, 25 °C, 16 h, 64%; (h) BBr3, CH2Cl2, ꢀ78 °C, 6 h, 71%.

440
I. N. I. N. Chaithanya Kiran et al. / Tetrahedron Letters 52 (2011) 438–440
out to furnish (+)-8-methoxygoniodiol (2) in 64% yield.13 Demeth-
ylation of 2 with BBr3 was successfully performed to afford (+)-
goniodiol (1) in 71% yield.14 The spectral data of both (+)-8-meth-
oxygoniodiol (2)17 and (+)-goniodiol (1)18 are in complete agree-
ment with the reported values.5,7
In summary, we have developed an efficient and straight-for-
ward enantioselective synthesis of two bioactive molecules
namely (+)-goniodiol (1) and (+)-8-methoxygoniodiol (2) with an
overall yield of 5.9% and 8.3%, respectively, that have been
achieved using two-stereocenter Co-catalyzed HKR of racemic
epoxide and Lewis acid-mediated diastereoselective allylation of
aldehyde. This methodology is also amenable for a viable synthetic
route in the synthesis of other diastereomers 3–5 of styryllactone
family by employing (R,R)-salen Co(OAc) complex for HKR and
BF3.OEt2, for Lewis acid-mediated diastereoselective allylation,
respectively.
M. J.; Edwards, A. J.; Karunaratne, O. P.; Smith, J. A.; Welling, L. L.; Willis, A. C.
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16. Spectral data of (2S,3R)-3-methoxy-3-phenyl-1,2-propanediol (7): ½a 2D5
ꢁ
= +113.95
Acknowledgments
(c 1.16, CHCl3); lit.8c a 2D5
½ ꢁ = +113.97 (c 1.016, CHCl3); 98% ee by chiral HPLC
analysis (Chiralcel OJ-H, n-hexane/iPrOH, 86:14, 0.5 mL/min) retention time
I.N.C.K. and R.S.R. thank CSIR, New Delhi for the award of re-
search fellowship and DST (No. SR/S1/OC-72/2006) New Delhi,
for financial support. The authors are thankful to Dr. B.D. Kulkarni,
Head, CEPD, for his constant support and encouragement.
24.15 (98.92%) and 25.50 (1.08%); IR (CHCl3): 720, 845, 1065, 1125, 1654, 2985,
3085, 3465 cmꢀ1 1H NMR (200 MHz, CDCl3): d 2.32 (br s, 2H), 3.30 (s, 3H),
;
3.52–3.78 (m, 3H), 4.32 (d, J = 9.2 Hz, 1H), 7.33–7.36 (m, 5H); 13C NMR
(50 MHz, CDCl3): d 57.16, 62.98, 74.53, 85.28, 127.34, 128.11, 128.51, 137.12.
Elemental analysis: C10H14O3 requires: C, 65.91; H, 7.74%. Found: C, 65.89; H,
7.37%.
17. Spectral data of 8-methoxygoniodiol (2): mp 98 °C (lit.5 mp 99–101 °C); ½a 2D5
ꢁ
= +
References and notes
23.8 (c 0.54, CHCl3); lit.5 a 2D5
½ ꢁ = +24.2 (c 0.68, CHCl3); IR (CHCl3): 757, 1057,
1109, 1380, 1719, 2909, 3445 cmꢀ1 1H NMR (200 MHz, CDCl3): d 2.25 (m, 1H),
;
1. Jewers, K.; Davis, J. B.; Dougan, J.; Manchanda, A. H.; Blunden, G.; Aye, K.;
Wetchapinan, S. Phytochemistry 1972, 11, 2025.
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A. T.; Lee, K. H. J. Nat. Prod. 1991, 54, 1077.
3. Sam, T.; Sew-Yeu, C.; Matsjeh, S.; Gan, E. K.; Razak, D.; Mohamed, A. L.
Tetrahedron Lett. 1987, 28, 2541.
4. (a) Talapatra, S. K.; Basu, D.; Deb, T.; Goswami, S.; Talapatra, B. Indian J. Chem.,
Sect B 1985, 24B, 29; (b) Lan, Y. H.; Chang, F. R.; Liaw, C. C.; Wu, C. C.; Chiang, M.
Y.; Wu, Y. C. Planta Med. 2005, 71, 153.
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C.; Hirai, S.; Hanaoka, M. J. Org. Chem. 1997, 2, 6619; (c) Banwell, M. G.; Coster,
2.74 (m, 1H), 3.20 (s, 3H), 3.54–3.57 (m, 1H), 4.29 (d, J = 8.6 Hz, 1H), 4.74 (ddd,
J = 12.0, 3.8, 1.9 Hz, 1H), 5.93–5.60 (dd, J = 9.6, 2.1 Hz, 1H), 6.74 (ddd, J = 9.6,
6.3, 2.1 Hz, 1H), 7.30–7.42 (m, 5H); 13C NMR (50 MHz, CDCl3): d 26.71, 56.62,
73.46, 75.61, 82.30, 119.35, 127.68, 128.16, 138.16, 143.92, 164.87. Elemental
analysis: C14H16O4 requires: C, 67.73; H, 6.50%. Found: C, 67.71; H, 6.39%.
18. Spectral data of (+)-goniodiol (1):
½
a D25
ꢁ
= +73.77 (c 0.24, CHCl3); lit.15
½
a D25
ꢁ
= +74.4 (c 0.3, CHCl3) IR (CHCl3): 1035, 1259, 1380, 1690, 3390 cmꢀ1
;
1H
NMR (200 MHz, CDCl3): d 2.20 (ddd, J = 3.6, 6.8, 16.5 Hz, 2H), 2.80–2.89 (m,
2H), 4.10 (t, J = 7.8 Hz, 1H), 5.10–5.24 (m, 2H), 6.03 (dd, J = 3.6, 7.2 Hz, 1H), 6.94
(ddd, J = 2.9, 6.4, 8.1 Hz, 1H), 7.27.7.38 (m, 5H); 13C NMR (50 MHz, CDCl3): d
26.48, 73.82, 75.06, 76.45, 121.03, 126.5, 128.47, 129.01, 138.51, 145.45,
163.18. Elemental analysis: C13H14O4 requires: C, 66.66; H, 6.02%. Found: C,
66.62; H, 6.01%.