An improved stereoselective total synthesis of (R)-rugulactone

Article abstract of DOI:10.1016/j.tetlet.2011.07.109

A novel route for the stereoselective total synthesis of (R)-rugulactone 1 has been developed, starting from substituted epoxide 4 and 3- phenylpropionaldehyde 5 employing Julia-Kocienski olefination as a key step to construct E-configured α,β-unsaturated keto-group. The overall yield of the synthesized rugulactone is 19.94% and is better than the reported methods.

Full text of DOI:10.1016/j.tetlet.2011.07.109

Tetrahedron Letters 52 (2011) 5133–5135
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An improved stereoselective total synthesis of (R)-rugulactone
⇑
Abhishek Goswami, Partha Pratim Saikia, Bishwajit Saikia, Devdutt Chaturvedi, Nabin C. Barua
Natural Products Chemistry Division, North East Institute of Science & Technology (CSIR), Jorhat 785006, Assam, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel route for the stereoselective total synthesis of (R)-rugulactone 1 has been developed, starting
from substituted epoxide 4 and 3-phenylpropionaldehyde 5 employing Julia-Kocienski olefination as a
Received 8 June 2011
Revised 22 July 2011
Accepted 23 July 2011
Available online 29 July 2011
key step to construct E-configured
a,b-unsaturated keto-group. The overall yield of the synthesized rug-
ulactone is 19.94% and is better than the reported methods.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Rugulactone
a
-Pyranon-2-one
NF- B inhibitor
Julia-Kocienski olefination
j
The natural products bearing 5,6-dihydro-
having substituted alkyl side chain at the C-6 position have attracted
muchattention since the last decade due to their medicinal potential
a
-pyrone skeleton
rugosa lipase.5c The other three syntheses involved mainly the ring
closing metathesis reaction employing diversity of the key inter-
mediates.5d,e Majority of the reported synthetic routes have several
limitations, such as the use of costly reagents, multiple synthetic
steps, and overall low yields of the desired product. Consequently,
there is continued interest in developing new and efficient syn-
thetic routes for the synthesis of rugulactone. Our group has been
working since the last several years on the synthesis of structurally
diverse biologically active natural products employing novel and
efficient synthetic routes.6 In this communication, we wish to
report a new and efficient total synthesis of (R)-rugulactone 1
starting from substituted epoxide 4 and 3-phenylpropionaldehyde
5 employing Julia-Kocienski olefination and Yamaguchi epoxide
opening as key steps.10
due to the Michael acceptor property of a,b-unsaturated a-pyrones
for the amino acid residues of the receptors.1 Due to the Michael
acceptor property of this class of molecules they have displayed
diverse arrays of potential biological activities, such as antitumor,
anti-inflammatory, antibacterial, antiviral, antifungal, antialzhei-
mer, antidiabetic, antioxidant, etc.2 The arylalkyl-substituted
a
,b-unsaturated d-lactones are omnipresent metabolites of the
evergreen trees of the genus Cryptocarya which are well known for
their potential medicinal properties.3 Recently, 6-arylalkyl-5,
6-dihydro-2H-pyran-2-one, (R)-rugulactone 1 was isolated from
the dichloromethane extract of Cryptocarya rugulosa, which was
found to inhibit nuclear factor-
is active against many types of cancer, exhibiting up to fivefold
induction of I B at 25
g/mL in human lymphoma cell lines.4 In view
of the potential biological activities displayed by this molecule,
several researchers have put their efforts toward the synthesis of
rugulactone involving novel strategies.
To the best of our knowledge, six syntheses of rugulactone have
already been explored in recent years.5 The first total synthesis
reported by Mohapatra et al. involves the ring closing metathesis
reaction and Horner–Wadsworth–Emmons reaction as key steps.5a
The second synthesis of Venkateswarlu et al. employed Keck’s
asymmetric allylation and Grubb’s cross metathesis reaction as
key steps,5b whereas the third synthesis reported by Fadnavis’s
group involved a chemoenzymatic pathway employing Candida
j
B (NF-kB) activation pathway and
Our retrosynthetic plan for the synthesis of target compound 1
is depicted in Scheme 1. We proposed that the synthesis of (R)-
rugulactone 1 could be achieved through the Julia-Kocienski olefin-
ation between aldehyde 14 and sulfone 3 to construct the C8–C9
trans double bond. Aldehyde 14 could be synthesized starting from
the epoxide 4. The synthesis of the sulfone derivative 3 could be
achieved from commercially available 3-phenyl propionaldehyde
5. It has been postulated that the stereochemistry at C-6 position
could be secured by the regioselective ring opening of epoxide 4.
To achieve the synthesis of target compound 1, 3-phenyl propi-
onaldehyde 5 was treated with vinylmagnesiumbromide in THF at
ꢀ30 °C to afford the allyl alcohol 6 in 90% yield (Scheme 2). Allyl
alcohol 6 was then protected as the MOM ether to furnish
compound 7. Oxidative cleavage of 7 with OsO4/NaIO4 in diox-
ane/H2O gave aldehyde 8, which without further purification was
reduced with sodium borohydride in methanol to afford the
primary alcohol 9. Alcohol 9 was converted into sulfide 10 by a
Mitsunobu reaction employing 1-phenyl-1H-tetrazole-5-thiol
j
l
⇑
Corresponding author. Tel.: +91 376 2371283; fax: +91 376 2370011.
E-mail
addresses:
ncbarua2000@yahoo.co.in,
ncbarua12@rediffmail.com
(N.C. Barua).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.109

5134
A. Goswami et al. / Tetrahedron Letters 52 (2011) 5133–5135
O
O
O
S
O
OMOM
O
O
N
O
O
+
N
N
N
H
Ph
1
14
3
O
O
OBn
4
5
Scheme 1. Retrosynthetic analysis of (R)-rugulactone 1.
OH
OMOM
Hydrolysis of the ester group of compound 12 proceeded with
in situ lactonization to deliver lactone 13. Removal of the benzyl
protecting group of compound 13 with DDQ in dichloromethane/
ii
i
O
7
water furnished the
a-pyrone subunit 2. Aldehyde 14 was pre-
5
6
pared by oxidation of 2 using Dess–Martin periodinane and was
used without further purification.
OMOM
H
OMOM
OH
iv
iii
v
After achieving the synthesis of both the fragments
(compounds 14 and 3), we then proceeded to the Julia-Kocien-
ski9 olefination (Scheme 4). Utilizing the robust and reliable pro-
cedure reported by Kocienski, sulfone 3 was deprotonated with
potassium bis(trimethylsilyl)amide (KHMDS) and subsequently
treated with crude aldehyde 14 to afford compound 15 in 65%
yield. MOM deprotection of 15 and subsequent oxidation of
the resulting crude alcohol with IBX furnished the target mole-
cule 1 in 92% yield. The physical and spectral properties of our
synthetic target compound 1 closely matched with the literature
data.
In conclusion, a convergent synthesis of (R)-rugulactone 1 has
been achieved starting from commercially available inexpensive
3-phenyl-1-propanal 5 and the known epoxide 4 employing Yam-
aguchi coupling and Julia-Kocienski olefination reaction as key
steps with the overall yield of 19.94%.
O
8
9
OMOM
S
MOMO
O
S
O
N
N
vi
N
N
N
N
N
N
Ph
10
Ph
3
Scheme 2. Reagents and conditions: (i) vinyl magnesium bromide, THF, ꢀ30 °C,
90%; (ii) MOMCl, DIPEA, 0 °C to rt, 90%; (iii) OsO4, 2,6-lutidine, NaIO4, dioxane/water
(3:1); (iv) NaBH4, MeOH, 0 °C, 95% over two steps; (v) TPP, PTSH, DIAD, THF, 0 °C to
rt, 85%; (vi) m-CPBA, CH2Cl2 0 °C, 90%.
(PT-SH) as the nucleophile in 85% yield. Sulfide 10 was then oxi-
dized with m-CPBA to yield the corresponding sulfone 3.
To achieve the synthesis of
a-pyrone subunit 2, the known
Acknowledgments
epoxide7 4 was coupled with ethyl propionate under Yamaguchi
coupling condition8 affording the corresponding propargylic alco-
hol 11 in 93% yield (Scheme 3). Subsequent hydrogenation of com-
pound 11 over Lindlar catalyst furnished unsaturated ester 12.
We are grateful to the Director, NEIST, Jorhat, for providing
facilities to carry out this work. A.G. thanks UGC, and P.P.S. and
B.S. thanks CSIR, New Delhi for research fellowships.
OH
EtOOC
OH
O
i
ii
OBn
EtOOC
O
OBn
OBn
12
4
11
O
O
iv
iii
v
O
O
O
O
OBn
OH
H
2
14
13
Scheme 3. Reagents and conditions: (i) Ethyl propionate, n-BuLi, BF3.OEt2, ꢀ78 °C, THF, 93%; (ii) H2, Lindlar catalyst, quinoline, EtOAc, 91%; (iii) 3% HCl in methanol, 90%; (iv)
DDQ, CH2Cl2–H20, 80%; (v) DMP, dry CH2Cl2, 0 °C to rt.
O
O
O
i
O
O
ii
O
OMOM
O
O
H
14
15
1
Scheme 4. Reagents and conditions: (i) 3, KHMDS, dry THF, ꢀ78 °C, 65%; (ii) (a) 37% HCl, ethanol, 40 °C, 93%; (b) IBX, dry DMSO, 92%.

A. Goswami et al. / Tetrahedron Letters 52 (2011) 5133–5135
(CHCl3)
= 3061, 2931 cmꢀ1
5135
m
;
1H NMR (300 MHz, CDCl3): d 7.67–7.59 (m,
References and notes
5H), 7.31–7.15 (m, 5H), 4.68 (d, J = 6.9 Hz, 1H), 4.55 (d, J = 7.0 Hz, 1H), 4.34–
4.26 (m, 1H), 4.03 (dd, J = 7.2, 14.8 Hz, 1H), 3.88 (dd, J = 4.4, 14.9 Hz, 1H), 3.35
(s, 3H), 2.72 (m, 2H), 2.08–2.01 (m, 2H); 13C NMR (CDCl3, 75 MHz): d 154.1,
140.7, 132.9, 131.6, 129.7, 128.6, 128.3, 126.2, 125.4, 96.5, 76.7, 71.9, 60.1,
56.2, 36.2, 30.7; MS (ESI): m/z = 425.13 (M++Na).
1. Buck, S. B.; Hardouin, C.; Ichikawa, S.; Soenen, D. R.; Gauss, C. M.; Hwang, I.;
Swinkle, M. R.; Bonness, K. M.; Honkanen, R. E.; Boger, D. L. J. Am. Chem. Soc.
2003, 125, 15695–15696.
2. Rychnovsky, S. D. Chem. Rev. 1995, 95, 2021–2040.
(5S)-7-Benzyloxy-5-hydroxy-hept-2-ynoic acid ethyl ester (11): ½a D20
ꢁ
= +1.17 (C
3. Marco, J. A.; Carda, M.; Murga, J.; Falomir, E. Tetrahedron 2007, 63, 2929–2958.
4. Meragelman, T. L.; Scudiero, D. A.; Davis, R. E.; Staudt, L. M.; McCloud, T. G.;
Cardellina, J. H., II; Shoemaker, R. H. J. Nat. Prod. 2009, 72, 336–339.
5. (a) Mohapatra, D. K.; Das, P. P.; Reddy, D. S.; Yadav, J. S. Tetrahedron Lett. 2009,
50, 5841–5944; (b) Reddy, D. K.; Shekhar, V.; Reddy, T. S.; Reddy, S. P.;
Venkateswarlu, Y. Tetrahedron: Asymmetry 2009, 20, 2315–2319; (c) Reddipalli,
G.; Venkataiah, M.; Fadnavis, N. W. Tetrahedron: Asymmetry 2010, 21, 320–324;
(d) Cros, F.; Pelotier, B.; Piva, O. Eur. J. Org. Chem. 2010, 5063–5070; (e) Reddy,
D. K.; Shekhar, V.; Prabhakar, P.; Babu, B. C.; Siddhardha, B.; Murthy, U. S. N.;
Venkateswarlu, Y. Eur. J. Med. Chem. 2010, 45, 4657–4663; (f) Allais, F.;
Aouhansou, M.; Majira, A.; Ducrot, P.-H. Synthesis 2010, 16, 2787–2793; (g)
Bose, D.; Fernandez, E.; Pietruszka, J. J. Org. Chem. 2011, 76, 3463–3469.
6. (a) Saikia, P. P.; Baishya, G.; Goswami, A.; Barua, N. C. Tetrahedron Lett. 2008, 49,
6508–6511; (b) Saikia, P. P.; Goswami, A.; Baishya, G.; Barua, N. C. Tetrahedron
Lett. 2009, 50, 1328–1330; (c) Boruwa, J.; Barua, N. C. Tetrahedron 2006, 62,
1193–1198; (d) Gogoi, N.; Boruwa, J.; Barua, N. C. Eur. J. Org. Chem. 2006, 1722–
1725; (e) Boruwa, J.; Gogoi, N.; Barua, N. C. Org. Biomol. Chem. 2006, 4, 3521–
3525.
1.0, CHCl3). IR (CHCl3): 3399, 2235, 1708 cmꢀ1 1H NMR (300 MHz, CDCl3): d
.
7.38–7.26 (m, 5H), 4.52 (s, 2H), 4.24 (q, J = 7.1 Hz, 2H), 4.06 (m, 1H), 3.77–3.65
(m, 2H), 3.37 (br s, 1H), 2.56–2.52 (m, 2H), 1.92–1.85 (m, 2H), 1.32 (t, J = 7.1 Hz,
3H). 13C NMR (CDCl3, 75 MHz): d 153.6, 137.6, 128.5, 128.4, 127.9, 85.6, 74.6,
73.4, 69.3, 69.1, 61.9, 35.3, 27.2, 14.0; MS (ESI): m/z = 276.1 (M+).
(5S, Z)-7-Benzyloxy-5-hydroxyhept-2-enoic acid ethyl ester (12): ½a D20
= ꢀ10.5 (C
ꢁ
0.85, CHCl3); IR (CHCl3) m ;
: 3422, 1716, and 1643 cmꢀ1 1H NMR (300 MHz,
CDCl3): d 7.34–7.3 (m, 5H), 6.41–6.35 (m, 1H), 5.92 (dd, J = 3, 15 Hz, 1H), 4.52
(s, 2H), 4.19 (q, J = 7.1 Hz, 2H), 4.01 (m, 1H), 3.74–3.65 (m, 2H), 3.28 (br s, 1H),
2.87–2.81 (m, 2H), 1.82–1.77 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3,
75 MHz): d 166.7, 146.2, 137.8, 128.4, 127.7, 121.4, 67.9, 66.7, 60.0, 36.5, 36.3,
14.2; MS (ESI): m/z = 278.4 (M+).
(6S, Z)-6-(2-Benzyloxyethyl)-5, 6-dihydro-pyran-2-one (13): ½a D20
= ꢀ42.9 (C 1.3,
ꢁ
CHCl3); IR (CHCl3) m ;
: 1719 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.35–7.32 (m,
5H), 6.91–6.85 (m, 1H), 6.05 (dd, J = 1.6, 9.7 Hz, 1H), 4.67–4.63 (m, 1H), 4.56 (d,
J = 5.31 Hz, 2H), 3.71–3.62 (m, 2H), 2.39–2.35 (m, 2H), 2.07–1.92 (m, 2H); 13C
NMR (CDCl3, 75 MHz): d 164.4, 145.2, 138.1, 128.4, 127.7, 121.3, 75.2, 73.3,
65.6, 35.1, 29.5; MS (ESI): m/z = 232.7 (M+).
7. Trost, B. M.; Amans, D.; Seganish, W. M.; Chung, C. K. J. Am. Chem. Soc. 2009,
131, 17087–17089.
8. Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391–394.
9. Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 26–28.
10. Selected analytical data for unknown compounds: (3-Methoxymethoxy-pent-4-
(6S, Z)-6-(2-Hydroxyethyl)-5, 6-dihydro-pyran-2-one (2): ½a D20
= ꢀ116.0 (C 1.25,
ꢁ
CHCl3); IR (CHCl3)
m ;
= 3399, 1701, 1622 cmꢀ1 1H NMR (300 MHz, CDCl3): d
6.95–6.88 (m, 1H), 6.06 (dd, J = 1.7, 9.7 Hz, 1H), 4.70–4.65 (m, 1H), 3.92–3.82
(m, 2H), 2.43–2.38 (m, 2H), 2.05–1.91 (m, 2H), 1.88 (br s, 1H). 13C NMR (CDCl3,
75 MHz): d 164.6, 145.6, 121.1, 75.6, 58.2, 37.3, 29.5; MS (ESI): m/z = 142.3
(M+).
enyl)-benzene (7): IR (CHCl3)
m ;
= 3063, 1603 cmꢀ1 1H NMR (300 MHz, CDCl3) d
7.30–7.15 (m, 5H), 5.77–5.66 (m, 1H), 5.25 (dd, J = 0.7, 5.4 Hz, 2H), 4.74 (d,
J = 6.9 Hz, 1H), 4.57 (d, J = 6.7 Hz, 1H), 4.04–4.02 (m, 1H), 3.39 (s, 3H), 2.76–
2.65 (m, 2H), 1.96–1.82 (m, 2H); 13C NMR (CDCl3, 75 MHz): d 142.0, 138.2,
128.7, 128.4, 125.8, 117.4, 93.9, 55.5, 37.2, 31.7. MS (ESI): m/z = 206.5 (M+).
(6R)-6-(4-Methoxymethoxy-6-phenyl-hex-2-enyl)-5,6-dihydro-pyran-pyran-2-
one (15): ½a 2D0
ꢁ
= +2.5 (C 0.6, CHCl3); IR (CHCl3): m ;
= 1735, 1601 cmꢀ1 1H NMR
(300 MHz, CDCl3): d 7.82–7.79 (m, 1H), 7.59 (dd, J = 7.5, 25.5 Hz, 1H), 7.30–7.18
(m, 5H), 5.75–5.66 (m, 1H), 5.25 (d, J = 14 Hz, 1H), 5.20 (m, 1H), 4.74 (d,
J = 6.6 Hz, 1H), 4.57 (d, J = 6.7 Hz, 1H), 4.05–4.02 (m, 1H), 3.39 (s, 3H), 2.76–
2.65 (m, 2H), 1.96–1.82 (m, 2H), 1.64 (m, 2H), 1.28 (m, 2H); 13C NMR (CDCl3,
75 MHz): d 142.0, 138.1, 137.5, 132.4, 130.0, 128.3, 128.2, 125.8, 117.4, 93.8,
55.5, 37.1, 31.7, 29.7; MS (ESI): m/z = 316.1 (M+).
2-Methoxymethoxy-4-phenylbutan-1-ol (9): IR (CHCl3)
m ;
= 3427, 3060 cmꢀ1 1H
NMR (300 MHz, CDCl3) d 7.30–7.16 (m, 5H), 4.78 (d, J = 6.9, 1H), 4.67 (d,
J = 6.9 Hz, 1H), 3.58–3.51 (m, 3H), 3.44 (s, 3H), 3.25 (br s, 1H), 2.76–2.64 (m,
2H), 1.85–1.76 (m, 2H); 13C NMR (CDCl3, 75 MHz): d 141.7, 128.4, 128.3, 126.2,
125.9, 97.0, 81.5, 65.6, 55.7, 33.3, 31.7. MS (ESI): m/z = 210.8 (M+).
(6R)-(4-Oxo-6-phenyl-hex-2-enyl)-5,6-dihydropyran-2-one (1): ½a D20
= ꢀ61.2 (C
ꢁ
5-(2-Methoxymethoxy-4-phenylbutylsulphanyl)-1-phenyl-1H-tetrazole (10): IR
0.5, CHCl3); IR (CHCl3)
m ;
= 3081, 1725, 1634 cmꢀ1 1H NMR (300 MHz, CDCl3): d
(CHCl3)
m ;
= 3060, 2927 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.58–7.52 (m,
7.39–7.12 (m, 5H), 6.95–6.84 (m, 1H), 6.81 (dt, J = 15.1 Hz, 7.3 Hz, 1H), 6.24 (d,
J = 14.9 Hz, 1 H), 6.01 (d, J = 9.1 Hz, 1H), 4.43 (m, 1H), 3.09–2.80 (m, 4H), 2.78–
2.48 (m, 2H), 2.42–2.29 (m, 2H); 13C NMR (75 MHz, CDCl3): d 199.0, 163.1, 144,
141.3, 140.3, 133.9, 129.1, 128.6, 126.5, 120.8, 75.4, 42.0, 36.9, 30.2, 283; MS
(ESI): m/z = 293.1 (M++Na).
5H), 7.30–7.16 (m, 5H), 4.76 (d, J = 6.9 Hz, 1H), 4.69 (d, J = 7.0 Hz, 1H), 4.01–
3.97 (m, 1H), 3.76 (dd, J = 4.7, 13.4 Hz, 1H), 3.63 (dd, J = 5.7, 13.4 Hz, 1H), 3.38
(s, 3H), 2.78–2.70 (m, 2H), 2.01–1.96 (m, 2H); 13C NMR (CDCl3, 75 MHz): d
154.4, 141.4, 133.6, 130.2, 129.8, 128.5, 128.3, 126.0, 123.8, 96.1, 75.4, 56.0,
37.9, 35.7, 31.4; MS (ESI): m/z = 371.7 (M+).
5-(2-Methoxymethoxy-4-phenylbutan-1-sulfonyl)-1-phenyl-1H-tetrazole (3): IR