Synthesis of a novel diarylheptanoid isolated from Zingiber officinale

Article abstract of DOI:10.1016/j.tetlet.2009.03.154

Syntheses of 4-acetoxy-2,6-disubstituted tetrahydropyrans via Prins cyclisation of homoallylic alcohols with benzylic aldehydes are described and the methodology is applied in the total synthesis of diarylheptanoid 1 confirming both the structure and abso

Full text of DOI:10.1016/j.tetlet.2009.03.154

Tetrahedron Letters 50 (2009) 3686–3689
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of a novel diarylheptanoid isolated from Zingiber officinale
*
Gregory D. Parker, Peter T. Seden, Christine L. Willis
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Syntheses of 4-acetoxy-2,6-disubstituted tetrahydropyrans via Prins cyclisation of homoallylic alcohols
with benzylic aldehydes are described and the methodology is applied in the total synthesis of diarylhep-
tanoid 1 confirming both the structure and absolute configuration of the natural product.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 14 January 2009
Revised 13 March 2009
Accepted 24 March 2009
Available online 27 March 2009
In a programme aimed at the discovery of novel compounds
from the Zingiberaceae species, the groups of Cheng and Zhao re-
ported the isolation of a new diarylheptanoid 1 from the methanol
extracts of Zingiber officinale collected in Yunnan Province, China.1
Whilst 1 showed no cytotoxicity against a human carcinoma cell
line or rat liver hepatocytes, it possessed potent antioxidant prop-
erties. The structure of the diarylheptanoid with three equatorial
substituents adorning a tetrahydropyran ring, was elucidated
through extensive spectroscopic studies. Whilst the (2S,4R,6S)
absolute stereochemistry is indicated in the structure of 1, and
ucts.3 The alternative disconnection gives homoallylic alcohol D
and protected trihydroxybenzaldehyde C as the electrophile. A
model study on the synthesis of racemic 4-acetoxytetrahydropyran
4 was undertaken to compare the two potential routes (Scheme 2).
Treatment of homoallylic alcohol 3 with dihydrocinnamaldehyde
and BF3ꢂOEt2 for 4 h at room temperature, with AcOH as the nucle-
ophile and TMSOAc as a fluoride trap in cyclohexane gave a mix-
ture of products including the required tetrahydropyran 4 (42%
yield) and the symmetrical products 5 and 6 arising from oxonia-
Cope/allyl transfer processes.
an optical rotation of ½a D
ꢀ
ꢁ32.5 (c 0.75 MeOH) was recorded, the
Reaction of alcohol 7 with 4-acetoxybenzaldehyde 8 under
identical conditions was found to be slow with significant quanti-
ties of starting materials being recovered after 4 h (Scheme 2).
However tetrahydropyran 4 was isolated as the sole heterocyclic
product. Interestingly, Rychnovsky4 has shown that symmetrical
products 11 and 12 are formed in the BF3ꢂOEt2-promoted reaction
of (S)-1-phenylbut-3-en-1-ol 9 (87% ee) with dihydrocinnamalde-
hyde; the major product was the unsymmetrical 4-acetoxytetra-
hydropyran 10 which was formed with some loss of
enantiopurity (68% ee) occurring during the cyclisation (Scheme 3).
Not only do the electronic properties of homoallylic alcohols
and aldehydes affect the reaction outcome, but also the conditions,
including acid used, solvent, temperature and the nucleophile em-
ployed, play an important role.5 For example, Rychnovsky reported
that reaction of benzylic alcohol 9 with dihydrocinnamaldehyde
and SnBr4 gave 4-bromotetrahydropyran 13 in 77% yield along
with a small amount (8%) of symmetrical product 14. The contrast-
ing results shown in Scheme 3 were attributed to the Prins cyclisa-
tion being much faster with SnBr4 than with BF3ꢂOEt2/AcOH/
TMSOAc and so suppressing the competing oxonia-Cope rear-
rangement.4 Thus, based on our model study and literature prece-
dent,3–5 the preferred pathway to our target diarylheptanoid 1
involved reaction of a functionalised benzaldehyde C and homoal-
lylic alcohol D (Scheme 1).
authors make no mention of the absolute configuration.
HO
OH
2
MeO
R
+
O
O
OH
R'
HO
6
4
2
1
Prins cyclisations are of value for the stereoselective synthesis
of tetrahydropyrans and have been used to good effect in natural
product synthesis.2 Using aldehydes and homoallylic alcohols as
precursors for the in situ generation of an unsaturated oxocarbeni-
um ion 2 required for the cyclisation, two disconnections of diaryl-
heptanoid 1 may be proposed (Scheme 1).
One approach would involve reaction of a benzylic homoallylic
alcohol A with aldehyde B. Choice of protecting groups for the aro-
matic alcohols is important as it has been shown that during Prins
cyclisations of benzylic alcohols adjacent to an electron-rich aro-
matic ring, solvolysis and oxonia-Cope rearrangements may occur
leading to racemisation and formation of a number of side prod-
Further model studies were undertaken to establish appropriate
conditions to introduce an oxygen nucleophile at C-4 of the target
trisubstituted tetrahydropyran. Trifluoroacetic acid has been used
in Prins cyclisations for the efficient synthesis of 4-hydroxy-
* Corresponding author.
E-mail address: chris.willis@bristol.ac.uk (C.L. Willis).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.154

G. D. Parker et al. / Tetrahedron Letters 50 (2009) 3686–3689
3687
OMe
OMe
PO
PO
PO
PO
OMe
O
HO
HO
OH
OH
H
O
C
D
A
+
+
OP
OH
1
OP
HO
O
H
B
Scheme 1. Retrosynthetic analysis of diarylheptanoid 1.
AcO
AcO
Ph
O
Ph
O
Ph
OH
Ph(CH2)2CHO
+
X
OAc
4 42%
5, X = OAc, 28%
6, X = F, 8%
3
HO
Ph
AcO
+
+
8, 26%
+
4, 34%
7, 31%
CHO
7
8
Reaction conditions: BF3·OEt2, AcOH, TMSOAc, cyclohexane, 4 h, rt
Scheme 2. Model cyclisation studies.
BF3·OEt2
AcOH
TMSOAc
Ph
OH
Ph
O
R
R
O
R
+
Ph
O
Ph
SnBr4
CH2Cl2
9
+
11% ee
9 87% ee
Br
cyclohexane
OAc
OAc
10 68% ee
+
11, R = (CH2)2Ph
12, R = Ph
13, R = (CH2)2Ph, 77%, 85% ee
14, R = Ph, 8%
Ph(CH2)2CHO
Ratio 10:11:12:9 4.0:1.2:1.0:1.6
Scheme 3. Prins cyclisations with homoallylic alcohol 9.4
2,3,6-trisubstituted6 and 4-hydroxy-2,6-disubstituted tetrahydro-
pyrans.7 In this case, however, treatment of 4-acetoxybenzalde-
hyde 8 and homoallylic alcohol 7 with TFA in CH2Cl2, and
subsequent base hydrolysis of the resultant ester, gave the re-
quired unsymmetrical 2,4,6-trisubstituted tetrahydropyran 15 in
only 34% yield accompanied by the symmetrical product 16 (31%
yield) and 4-hydroxybenzaldehyde (31% yield) arising from oxo-
nia-Cope rearrangement/allyl transfer processes (Scheme 4). Simi-
larly reaction of homoallylic alcohol 18 and benzaldehyde gave the
two tetrahydropyrans 19 and 20 in approximately 1:1 ratio.
Next the BF3ꢂOEt2-mediated reactions of homoallylic alcohol 18
with either 4-acetoxybenzaldehyde 8 or benzaldehyde 17 were
investigated using CH2Cl2 as the solvent and were found to be fas-
ter than in cyclohexane. After 4 h at room temperature, acetates 21
and 23 were isolated in good yields (68% and 70%, respectively),
accompanied by tetrahydropyrans 22 and 24 arising from attack
of fluoride at C-4. No symmetrical products were detected.
in 65% yield, accompanied by 4-fluorotetrahydropyran 28 (15%).
Hydrogenolysis of the benzyl ether-protecting group of 27 gave
alcohol 29 in 99% yield.
Hydrolysis of the acetate-protecting groups of 29 would give
diarylheptanoid 1 in racemic form. However, there was potential
to shorten the synthetic route by using a single deprotection step
if the phenol of the homoallylic alcohol was protected as an ace-
tate, rather than a benzyl ether. Thus (S)-homoallylic alcohol 34
was synthesised from commercially available 3-(4-hydroxy-
phenyl)propionic acid 30 via aldehyde 32 as shown in Scheme 6.
Firstly, alcohol 30 was acetylated to give 31 prior to selective
reduction of the carboxylic acid using borane–THF complex. Swern
oxidation of the resultant primary alcohol gave aldehyde 32. (S)-
Homoallylic alcohol 34 was prepared in 53% yield and 91% ee by
treatment of aldehyde 32 with Loh’s chiral allyl transfer reagent
33.8 Mosher’s method9 was used to confirm the (S)-configuration
of the novel homoallylic alcohol 34.
Having established suitable conditions for the key Prins cyclisa-
tion, this methodology was applied to the total synthesis of the tar-
get diarylheptanoid (Scheme 5). Aldehyde 26, prepared by
acetylation of commercially available diol 25, and homoallylic
alcohol 18 were treated under the BF3ꢂOEt2-mediated conditions
in CH2Cl2. The required 4-acetoxytetrahydropyran 27 was isolated
Prins cyclisation of homoallylic alcohol 34 and aldehyde 26
gave the required tetrahydropyran 35 in 81% yield and the 4-fluoro
derivative 36 (16%). From the coupling constants in the 1H NMR
spectrum of 35 it was evident that all three substituents were in
an equatorial orientation.10 Chiral HPLC analysis of both 35 and
36 revealed an 85% ee, indicating a small loss of enantiopurity dur-

3688
G. D. Parker et al. / Tetrahedron Letters 50 (2009) 3686–3689
R'
R'
R'
R'
R
R
O
O
X
HO
O
+
+
H
X
Reaction Conditions: i, TFA, CH2Cl2, 4 h, rt; ii, K2CO3, MeOH
15, R = OH, R' = H, X = OH 34%
19, R = H, R' = OBn, X = OH, 50%
7 R' = H
16, R' = H, X = OH 31%
8, R = OAc
17, R = H
20, R' = OBn, X = OH 48%
18 R' = OBn
Reaction Conditions: BF3·OEt2, AcOH, TMSOAc, CH2Cl2, 4 h, rt
21, R = X = OAc, R' = OBn, 68%
22, R = OAc, R' = OBn, X = F, 14%
18, R' = OBn
8, R = OAc
23, R = H, R' = OBn, X = OAc 70%
24, R = H, R' = OBn, X = F, 20%
18, R' = OBn
17, R = H
Scheme 4. Prins cyclisations.
OMe
OMe
OMe
BF3·OEt2
TMSOAc
AcOH
AcO
AcO
OBn
+
OBn
AcO
AcO
OBn
AcO
AcO
O
HO
O
O
+
CH2Cl2
H
OAc
27
F
28
26
18
65%
15%
O,Et 3N
Ac2
H2,Pd/C,
EtOH,2h
99%
DMAP,CH2Cl2
96%
OMe
OMe
AcO
AcO
OH
HO
HO
O
O
H
OAc
25
29
99%
Scheme 5. Synthesis of tetrahydropyran 29.
HO
AcO
i) NaOH, Ac2O
H2O, 16 h
AcO
i. BH3·THF
OH
OH
O
ii DMSO, (COCl)2
Et3N, CH2Cl2, 97%
ii) HClaq.
O
O
H
30
32
31
96%
CSA(cat.)
CH2Cl2
53%
OH
OH
OMe
OMe
AcO
OAc
HO
HO
OH
33
BF3·OEt2,TMSOAc
AcOH, CH2Cl2, 4 h
K2CO3
MeOH
O
R
AcO
AcO
O
OMe
AcO
OH
35, R = OAc, 81% yield, 85% ee
1
80%
O
34
91% ee
AcO
+
26
H
36, R = F, 16% yield, 85% ee
Scheme 6. Synthesis of diarylheptanoid 1.

G. D. Parker et al. / Tetrahedron Letters 50 (2009) 3686–3689
3689
6. Barry, C. S.; Bushby, N.; Harding, J. R.; Willis, C. L. Org. Lett. 2005, 7, 2683; Yadav,
J. S.; Purushothama, P.; Sridhar, R. M.; Prasad, R. A. R. Tetrahedron Lett. 2008, 49,
5427.
7. Yadav, J. S.; Kumar, N. N.; Reddy, M. S.; Prasad, A. R. Tetrahedron 2007, 63, 2689;
Vintonyak, V. V.; Maier, M. E. Org. Lett. 2008, 10, 1239.
ing the cyclisation step. Hydrolysis of the four acetate groups of 35
using potassium carbonate in methanol gave diarylheptanoid 1 in
80% yield. The spectroscopic data for the synthetic sample of 1 and
the natural product1 were identical. Synthetic 1 gave an optical
8. Lee, C. H. A.; Loh, T.-P. Tetrahedron Lett. 2004, 45, 5819.
9. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
rotation of ½aꢀD ꢁ22 (c 1.0 MeOH) which, taking into account the
85% ee, is in accord with the value of ½aꢀD ꢁ32.5 (c 0.75 MeOH) re-
10. Experimental procedure for the Prins cyclisation to 35 and 36: A stirred solution
of aldehyde 26 (0.27 g, 1.07 mmol), homoallylic alcohol 34 (0.25 g, 1.07 mmol),
TMSOAc (0.80 mL, 5.35 mmol) and AcOH (0.43 mL, 7.49 mmol) in dry CH2Cl2
(15 mL) was cooled to 0 °C and treated dropwise with BF3ꢂOEt2 (0.27 mL,
2.13 mmol) under an atmosphere of nitrogen. After stirring at 0 °C for 0.5 h the
mixture was allowed to warm to room temperature and was stirred for a
further 3.5 h before the addition of NaHCO3 solution (30 mL satd aq) and
CH2Cl2 (15 mL). The layers were separated and the aqueous phase extracted
with CH2Cl2 (3 ꢃ 20 mL). The combined organic extracts were washed with
water (40 mL) and brine (40 mL), dried over MgSO4 and concentrated in vacuo
to give an orange oil (0.66 g). The crude product was purified by flash
ported for the natural product and hence the absolute configura-
tion is confirmed to be (2S,4R,6S).1
In conclusion, conditions for the preparation of 4-hydroxy- and
4-acetoxy-2,6-disubstituted tetrahydropyrans via Prins cyclisation
of homoallylic alcohols with benzylic aldehydes have been investi-
gated. It was established that use of BF3ꢂOEt2, AcOH and TMSOAc in
CH2Cl2 gave unsymmetrical 4-acetoxytetrahydropyrans in good
yields. Interestingly, under these conditions, significant amounts
(14–20% yield) of the corresponding 4-fluorides were isolated
whereas in previous studies using cyclohexane as the solvent3,4
either less amounts (or none) of the 4-fluorotetrahydropyrans
were isolated and we are currently investigating this further. The
first enantioselective total synthesis of diarylheptanoid 1 has been
completed confirming the reported structure and absolute
stereochemistry.
chromatography
acetoxytetrahydropyran 35 as
fluorotetrahydropyran 36 as a colourless oil (0.085 g, 16%).
Compound 35: Rf = 0.15 (35% EtOAc/petrol); ½a D ꢁ20 (c 1.0, CHCl3); chiral
eluting
with
35%
EtOAc/petrol
to
give
4-
a
colourless oil (0.46 g, 81%) and 7-
ꢀ
HPLC (Chiralcel OD-H, 50-80% IPA/hexane over 80 min, 0.25 mL/min), 48.0 min
(major), 70.3 min (minor); mmax (neat)/cmꢁ1 3021 (CH), 2939 (CH), 2857 (CH),
1768 (C@O), 1741 (C@O), 1716 (C@O), 1613 (C@C), 1506, 1368, 1184, 1090,
1011, 908, 751, 730; dH (400 MHz, CDCl3) 1.41 (1H, dt, J 12.2, 11.1 Hz, 3-Hax),
1.51 (1H, dt, J 12.2, 11.1 Hz, 5-Hax), 1.80 (1H, dddd, J 13.7, 9.4, 7.3, 4.2 Hz, 10-
HH), 1.98 (1H, dddd, J 13.7, 9.2, 8.2, 5.1 Hz, 10-HH), 2.02 (1H, m, 3-Heq), 2.04
(3H, s, –OAc), 2.26 (1H, m, 5-Heq), 2.27 (3H, s, –OAc), 2.28 (3H, s, –OAc), 2.29
(3H, s, –OAc), 2.71 (1H, ddd, J 14.1, 9.2, 7.3 Hz, 20-HH), 2.81 (1H, ddd, J 14.1, 9.4,
5.1 Hz, 20-HH), 3.51 (1H, dddd, J 11.1, 8.2, 4.2, 1.8 Hz, 2-H), 3.84 (3H, s, –OMe),
4.38 (1H, dd, J 11.1, 2.0 Hz, 6-H), 5.00 (1H, app. tt, J 11.1, 4.6 Hz, 4-H), 6.80 (1H,
d, J 1.9 Hz, 2000-H or 6000-H), 6.87 (1H, d, J 1.9 Hz, 2000-H or 6000-H), 6.98 (2H, m,
300H), 7.17 (2H, m, 200H); dC (100 MHz, CDCl3) [20.4, 20.7, 21.2, 21.3 (4 ꢃ –
OOCCH3)], 31.1 (C-20), 37.0 (C-3), 37.5 (C-10), 39.2 (C-5), 56.3 (–OMe), 70.4 (C-
4), 74.7 (C-2), 76.4 (C-6), [107.3, 112.4 (C-2000 and C-6000)], 121.5 (C-300), 129.4
(C-200), [131.6, 139.5, 140.6, 143.2, 148.9, 152.3 (C-Ar)], [168.0, 168.3, 169.7,
170.6 (4 ꢃ –OOCCH3)]; found (ESI) 551.1883 [MNa]+, (C28H32O10Na requires
551.1888).
Acknowledgement
We are grateful to the EPSRC for funding to G.D.P. and P.T.S.
References and notes
1. Tao, Q. F.; Xu, Y.; Lam, R. Y. Y.; Schneider, B.; Dou, H.; Leung, P. S.; Shi, S. Y.;
Zhou, C. X.; Yang, L. X.; Zhang, R. P.; Xiao, Y. C.; Wu, X.; Stockigt, J.; Zeng, S.;
Cheng, C. H. K.; Zhao, Y. J. Nat. Prod. 2008, 71, 12.
Compound 36: Rf = 0.21 (35% EtOAc/petrol);); ½aꢀD ꢁ46 (c 1.0, CHCl3); Chiral
HPLC (Chiralcel OD-H, 50–80% IPA/hexane over 80 min, 0.25 mL/min), 43.7 min
(major), 61.0 min (minor); mmax (neat)/cmꢁ1 3022 (CH), 2933 (CH), 2857 (CH),
1766 (C@O), 1613 (C@C), 1506, 1368, 1183, 1090, 1008, 750; dH (400 MHz,
CDCl3) 1.52 (1H, app. quint., 3JHF 11.2, JHH 11.2 Hz, 3-Hax), 1.65 (1H, app. quint.,
3JHF 11.2, JHH 11.2 Hz, 5-Hax), 1.83 (1H, dddd, J 13.7, 9.1, 7.7, 4.2 Hz, 10-HH), 2.00
(1H, dtd, J 13.7, 8.6, 5.4 Hz, 10-HH), 2.14 (1H, m, 3-Heq), 2.28 (3H, s, –OAc), 2.29
(3H, s, –OAc), 2.30 (3H, s, –OAc), 2.37 (1H, m, 5-Heq), 2.73 (1H, ddd, J 14.1, 8.6,
7.7 Hz, 20-HH), 2.81 (1H, ddd, J 14.1, 9.1, 5.4 Hz, 20-HH), 3.43 (1H, dddt, JHH 11.2,
2. For recent examples see: Cossey, K. N.; Funk, R. L. J. Am. Chem. Soc. 2004, 126,
12216; Chan, K.-P.; Loh, T.-P. Org. Lett. 2005, 7, 4491; Chan, K.-P.; Ling, Y. H.;
Loh, T.-P. Chem. Commun. 2007, 939; Dalgard, J. E.; Rychnovsky, S. D. Org. Lett.
2005, 7, 1589; Van Orden, L. J.; Patterson, B. D.; Rychnovsky, S. D. J. Org. Chem.
2007, 72, 5784; Cheung, L. L.; Marumoto, S.; Anderson, C. D.; Rychnovsky, S. D.
Org. Lett. 2008, 10, 3101; Tian, X.; Jaber, J. J.; Rychnovsky, S. D. J. Org. Chem.
2006, 71, 3176; Reddy, M. S.; Narender, M.; Rao, K. R. Tetrahedron 2007, 63,
11011; Ko, H. M.; Lee, D. G.; Kim, M. A.; Kim, H. J.; Park, J.; Lah, M. S.; Lee, E. Org.
Lett. 2007, 9, 141; Kwon, M. S.; Woo, S. K.; Na, S. W.; Lee, E. Angew. Chem., Int. Ed
2008, 47, 1733; Seden, P. T.; Charmant, J. H. P.; Willis, C. L. Org. Lett. 2008, 10,
1637; Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D. J. Am. Chem. Soc. 2008, 130,
16864; Barry, C. S.; Elsworth, J. D.; Seden, P. T.; Bushby, N.; Harding, J. R.; Alder,
R. W.; Willis, C. L. Org. Lett. 2006, 8, 3319; Bahnk, K. B.; Rychnovsky, S. D. J. Am.
Chem. Soc. 2008, 130, 13177.
3. Crosby, S. R.; Harding, J. R.; King, C. D.; Parker, G. D.; Willis, C. L. Org. Lett. 2002,
4, 577; Crosby, S. R.; Harding, J. R.; King, C. D.; Parker, G. D.; Willis, C. L. Org. Lett.
2002, 4, 3407; Barry, C. S.; Bushby, N.; Harding, J. R.; Hughes, R. A.; Parker, G. D.;
Roe, R.; Willis, C. L. Chem. Commun. 2005, 3727.
4. Marumoto, S.; Jaber, J. J.; Vitale, J. P.; Rychnovsky, S. D. Org. Lett. 2002, 4, 3919.
5. Jasti, R.; Rychnovsky, S. D. J. Am. Chem. Soc. 2006, 128, 13640; Bahnk, K. B.;
Rychnovsky, S. D. Chem. Commun. 2006, 2388.
4
8.6, 4.2, 2.0 Hz, JHF 2.0 Hz, 2-H), 3.86 (3H, s, –OMe), 4.30 (1H, dt, JHH 11.2,
4
2
2.0 Hz, JHF 2.0 Hz, 6-H), 4.78 (1H, dtt, JHF 48.9 Hz, JHH 11.1, 4.7 Hz, 4-H), 6.86
(1H, d, J 1.8 Hz, 2000-H or 6000-H), 6.89 (1H, d, J 1.8 Hz, 2000-H or 6000-H), 6.99 (2H,
m, 300-H), 7.18 (2H, m, 200-H); dC (100 MHz, CDCl3) [20.4, 20.8, 21.2, (3 ꢃ –
OOCCH3)], 31.1 (C-20), 37.4 (d, 4JCF 1.5 Hz, C-10), 38.3 (d, 2JCF 16.1 Hz, C-3), 40.3
2
1
3
(d, JCF 17.7 Hz, C-5), 56.4 (-OMe), 72.4 (d, JCF 159.9 Hz, C-4), 74.1 (d, JCF
3
11.5 Hz, C-2), 76.0 (d, JCF 12.3 Hz, C-6), [107.4, 112.5 (C-2000 and C-6000)], 121.5
4
(C-300), 129.5 (C-200), [131.2, 139.4 (C–Ar)], 140.3 (d, JCF 2.2 Hz, C-1000), [143.3,
148.9, 152.4 (C-Ar)], [168.0, 168.4, 169.8 (3 ꢃ –OOCCH3)]; dF (282.8 MHz)
ꢁ170.6 (br d, JHF 49.0 Hz); found (ESI) 511.1739 [MNa]+, (C26H29O8FNa requires
511.1739).