A carbohydrate-based approach for the total synthesis of strictifolione

Article abstract of DOI:10.1016/j.tetlet.2005.04.031

A chiral pool approach starting with D-glucose, using the Yamaguchi protocol and a Z-selective HWE reaction followed by lactonization, has been applied to execute the total synthesis of strictifolione.

Full text of DOI:10.1016/j.tetlet.2005.04.031

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4073–4075
A carbohydrate-based approach for the total synthesis of
strictifolione
C. V. Ramana,a,* N. Raghupathi,a Mukund K. Gurjara and Mukund S. Chorghadeb
aNational Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
bChorghade Enterprise, 14, Carlson Circle, Natick, MA 01760, USA
Received 19 February 2005; revised 31 March 2005; accepted 5 April 2005
Abstract—A chiral pool approach starting with D-glucose, using the Yamaguchi protocol and a Z-selective HWE reaction followed
by lactonization, has been applied to execute the total synthesis of strictifolione.
Ó 2005 Elsevier Ltd. All rights reserved.
Strictifolione 1 belongs to the family of 5,6-dihydro-d-
pyrone derivatives having an alkyl side chain at the C6
position.1 The broad range of biological activities re-
ported for this class of compounds has been ascribed
to their inherent tendency to act as good Michael accep-
tors. Strictifolione was isolated by Aimi and co-workers
from the stem bark of Cryptocarya strictifolia that grows
in the Indonesian tropical rainforests.2 The relative and
the absolute configuration of strictifolione were revised
by the same group after accomplishing its first total syn-
thesis.3 Later, asymmetric syntheses, primarily with a
RCM as one of the key reactions, have been reported.4
O
2
3
4
O
OH OH
cis-HWE
2'
8'
Reaction
6
Ph
Ph
3'
5'
1'
Yamaguchi
Protocol
Strictifolione (1)
OR'
OR OH
OR''
2
OBz
O
OTBS
As a part of our longstanding interest in the synthesis of
bioactive natural products using the chiron approach,5
we have taken up the total synthesis of strictifolione 1.
As shown in Figure 1, the disconnection process began
with two bonds at C(3)–C(4) and C(20)–C(30), each of
which could be realized by a cis-HWE reaction and a
Yamaguchi approach, respectively. This led to the key
intermediate 2 whose preparation by a convergent ap-
proach would involve the intermediates 3 and 4. The
intermediate 3 was envisaged from D-glucose, while the
chiral propargyl alcohol 4 could be produced from the
epoxy chloride 6 by a double elimination protocol.
+
Ph
OPMB
3
4
Ph
O
O
Cl
PMBO
O
O
6
5
D-Glucose
Figure 1. Retrosynthetic analysis for strictifolione.
isopropylidene-a-D-glucofuranose 7 from D-glucose.
Selective deprotection of the 5,6-O-isopropylidene
group, sodium periodate mediated oxidative cleavage
and Wittig olefination with benzyltriphenylphosphorane
furnished an impure mixture of the styrene derivative 8.
Subsequent hydrogenation of 8 in the presence of
Raney-Ni and ethanol at 60 psi gave 5, whose spectral
and analytical data were in agreement with the assigned
The synthesis of fragment 3 began by following the
literature procedure6 to prepare 3-deoxy-1,2;5,6-di-O-
Keywords: Strictifolione; D-Glucose; Double elimination; Horner–
Wadsworth–Emmons reaction; Yamaguchi protocol; Lactonization.
*
Corresponding author. Tel.: +91 20 25882456; fax: +91 20
25893614; e-mail: chepuri@dalton.ncl.res.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.031

4074
C. V. Ramana et al. / Tetrahedron Letters 46 (2005) 4073–4075
structure.7a Cleavage of the 1,2-O-isopropylidene group
of 5 in refluxing 30% aq AcOH followed by reduction
with LiAlH4 in THFprovided the triol 9 (Scheme 1).
THFat À78 °C. This protocol resulted in the formation
of the advanced intermediate 2. The spectral and analyt-
ical profiles of 2 were in agreement with the assigned
structure.12 The reduction of C„C to the corresponding
E-olefin with concomitant de-benzoylation occurred
when 2 was treated with Redal-H13 in ether at À20 °C.
The required product 13 was isolated and consequently
transformed into the isopropylidene derivative 14 with
2,2-dimethoxypropane-catalytic CSA.14 In the 13C
NMR of 14, the acetonide methyl groups resonated to-
gether at 24.9 ppm indicating a 1,3-anti-relationship.15
This was further substantiated by the appearance of
the quaternary carbon in the downfield region (100.3
ppm).
Our next target was to invert the center at C-4 for which
the selective protection of the 1,2-glycol unit of 9 was first
carried out using 3-pentanone and catalytic CSA. The
expected dioxolane derivative 10 was obtained exclu-
sively leaving the 4-hydroxy group free. The Mitsunobu
reaction of 10 in the presence of TPP, DEAD, and ben-
zoic acid followed by hydrolysis of dioxolane ring gave
the diol 11. This was treated with TsCl, Bu2SnO, and tri-
ethylamine in CH2Cl2, which resulted in the formation of
the monotosyl derivative whose exposure to NaH in
THFafforded the desired epoxy derivative 3.7b
Our next concern was to install the dihydropyran ring.
The PMB group was cleaved using DDQ in CH2Cl2–
H2O and then the free hydroxyl group of 15 was succes-
sively subjected to Swern oxidation and HWE reaction
with ethyl (di-o-tolylphosphono)acetate16 and NaH in
THFto obtain the Z-unsaturated ester 16 exclusively.17
Among a few reagents examined, PPTS in ethanol18 at
55 °C effectively deprotected both the TBS and the aceto-
nide groups. Moreover, the lactonization step also took
place to complete the total synthesis of strictifolione 1.
The physical and spectroscopic data of the synthetic
The synthesis of alkyne 4 began with the known8 epox-
ide 12, which upon chlorination9 in refluxing CCl4 and
TPP gave the chloroepoxide 6. This was subjected to
double elimination reaction10 by using excess n-BuLi
in THFat À40 °C and the resulting propargyl alcohol
was protected as the TBS-ether 4 (Scheme 2).
Having now access to both the fragments 3 and 4, the
Yamaguchi protocol11 for C–C bond formation was
investigated in the presence of n-BuLi, BF3ÆEt2O in
O
Ph
Ph
a-c
O
OH OH
O
O
O
d
e, f
ref 6
OH
D-Glucose
Ph
O
O
O
O
O
O
9
7
8
5
g
Et
Et
O
OBz
OH
h, i
OBz
j, k
OH
O
O
OH
Ph
Ph
Ph
3
11
10
Scheme 1. Reagents and conditions: (a) 30% AcOH, rt, 75%; (b) NaIO4 on silica gel, CH2Cl2, 96%; (c) C6H5CH2P+Ph3BrÀ, n-BuLi, THF, 0 °C ! rt,
67%; d) Raney-Ni, ethanol, 60 psi, 98%; (e) 30% AcOH, reflux, 72%; (f) LiAlH4, THF, rt, 92%; (g) 3-pentanone, CSA, 85%; (h) DEAD, TPP, benzoic
acid, THF, 91%; (i) PTSA, methanol, 74%; (j) TsCl, Bu2SnO, triethylamine, CH2Cl2, rt, 89%; (k) NaH, THF, 0 °C, 94%.
OTBS
OBz O
a
b, c
O
O
+
PMBO
OPMB
PMBO
O
OH
PMBO
f
Cl
Ph
12
14
6
4
3
d
OTBS
O
OTBS
OH OH
OTBS
e
OBz OH
OPMB
O
Ph
OPMB
OH
Ph
Ph
13
2
g
O
O
OTBS
O
O
OTBS
i
OH OH
O
h
Ph
CO2Et
Ph
Ph
15
16
Strictifolione (1)
Scheme 2. Reagents and conditions: (a) TPP, CCl4, reflux, 87%; (b) n-BuLi, THF, À40 °C, 79%; (c) TBSCl, imidazole, CH2Cl2, rt, 81%; (d) n-BuLi,
BF3ÆEt2O, THF, À78 °C, then 3, 85%; (e) red-Al, ether, À20 °C, 73%; (f) 2,4-DMP, CSA, acetone, 95%; (g) DDQ, DCM–water (9:1), 86%; (h) (i)
(COCl)2, DMSO, Et3N, CH2Cl2, À78 °C; (ii) ethyl (di-o-tolylphosphono)acetate, NaH, THF, 0 ! À78 °C, overall 81%; (i) PPTS, ethanol, 55 °C,
67%.

C. V. Ramana et al. / Tetrahedron Letters 46 (2005) 4073–4075
4075
375–382; (c) Lee, J. B.; Nolan, T. J. Can. J. Chem. 1966,
44, 1331.
10. (a) Takano, S.; Samizu, K.; Sugahara, T.; Ugasawara, K.
J. Chem. Soc., Chem. Commun. 1989, 1344–1345; (b)
Yadav, J. S.; Deshpande, P. K.; Sharma, G. V. M.
Tetrahedron 1990, 46, 7033–7046.
sample 1 were in good agreement with the reported data
25
D
of natural strictifolione {½aꢀ +61 (c 0.6, CHCl3); lit.2
25
D
CHCl3)}.
25
D
½aꢀ +81.5 (c 0.52, CHCl3); lit.4c ½aꢀ +54.1 (c 0.33,
In summary, the total synthesis of strictifolione using a
combination of chiral pool approach and an asymmetric
epoxidation reaction has been accomplished.
11. Yamguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391–
394.
25
12. Spectral data of compound 2: ½aꢀD 3.5 (c 1, CHCl3). 1H
NMR (500 MHz, CDCl3) d: 8.04 (br dt, J = 7.6, 1.5 Hz,
2H), 7.58 (br t, J = 7.5 Hz, 1H), 7.45 (br t J = 7.5 Hz, 2H),
7.27–7.22 (m, 4H), 7.18–7.15 (m, 3H), 6.84 (br dd, J = 8.5,
2.1 Hz, 2H), 5.41–5.35 (m, 1H), 4.57–4.51 (m, 1H), 4.42–
4.36 (m, 2H), 3.78 (s, 3H), 3.73–3.68 (m, 1H), 3.58–3.52 (m,
2H), 2.79–2.66 (m, 2H), 2.46–2.40 (m, 1H), 2.36–2.32 (m,
1H), 2.16–2.09 (m, 1H), 2.04–1.99 (m, 2H), 1.93–1.90
(m, 2H), 1.77–1.72 (m, 1H), 0.87 (br s, 9H), 0.09 (s, 3H),
0.08 (s, 3H). 13C NMR (125 MHz, CDCl3) d: À5.1 (q),
À4.6 (q), 18.2 (s), 25.6 (q), 25.8 (q), 27.2 (t), 31.9 (t), 36.8 (t),
38.9 (t), 41.9 (t), 55.2 (q), 60.1 (d), 66.0 (t), 66.1 (d), 71.7 (d),
72.6 (t), 80.5 (s), 84.08 (s), 113.7 (d), 125.9 (d), 128.3 (d),
128.4 (d), 128.4 (d), 129.22 (d), 129.7 (d), 129.8 (d), 130.5
(d), 133.2 (d), 141.2 (s), 159.1 (s), 167.4 (s). Anal. Calcd for
C38H50O6Si: C, 72.34; H, 7.99. Found: C, 72.13; H, 8.17.
13. Crousse, B.; Alami, M.; Linstrumelle, G. Synlett 1997,
992–994.
Acknowledgements
S.R. thanks CSIR, New Delhi for financial assistance in
the form of a research fellowship.
References and notes
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S. A.; Aimi, N. Phytochemistry 2000, 54, 989–993.
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A.; Takayama, H.; Aimi, N. Tetrahedron Lett. 2002, 43,
8657–8660.
4. (a) Tosaki, S.-Y.; Nemoto, T.; Ohshima, T.; Shibasaki, M.
Org. Lett. 2003, 5, 495–498; (b) Bouz, B. S.; Cossy, J. Org.
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5. (a) Gurjar, M. K.; Khaladkar, T. P.; Borhade, R. G.;
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Gurjar, M. K.; Nagaprasad, R.; Ramana, C. V. Tetrahe-
dron Lett. 2003, 44, 2873–2875; (c) Gurjar, M. K.;
Karmakar, S.; Mohapatra, D. K. Tetrahedron Lett.
2004, 45, 4525–4526.
25
14. Spectral data of compound 14: ½aꢀD 10.3 (c 1.1, CHCl3). IR:
3027, 1613, 1586, 1248, 1092, 836 cmÀ1 1H NMR
.
(500 MHz, CDCl3) d: 7.25–7.23 (m, 4 H), 7.19–7.14 (m,
3H), 6.88 (d, J = 8.6 Hz, 2H), 5.52 (dt, J = 15.4, 6.8 Hz,
1H), 5.45 (dd, J = 15.4, 6.2 Hz, 1H), 4.42 (d, J = 11.5 Hz,
1H), 4.36 (d, J = 11.5 Hz, 1H), 4.24 (br q, J = 6.2 Hz, 1H),
3.83–3.78 (m, 1H), 3.79 (s, 3H), 3.76–3.70 (m, 1H), 3.51
(dt, J = 9.2, 6.8 Hz, 1H), 3.44 (dt, J = 9.2, 6.2 Hz, 1H),
2.75 (ddd, J = 13.7, 9.3, 5.3 Hz, 1H), 2.60 (ddd, J = 13.7,
8.9, 7.2 Hz, 1H), 2.20 (dt, J = 13.7, 6.5 Hz, 1H), 2.12 (dt,
J = 13.7, 6.5 Hz, 1H), 1.86–1.78 (m, 1H), 1.76–1.69 (m,
3H), 1.58–1.55 (m, 2H), 1.34 (s, 3H), 1.32 (s, 3H), 0.87 (s,
9H), 0.03 (s, 3H), 0.01 (s, 3H). 13C NMR (125 MHz,
CDCl3) d: À4.8 (q), À4.2 (q), 18.2 (s), 24.9 (q), 25.9 (q),
31.7 (t), 37.5 (t), 38.2 (t), 38.4 (t), 38.6 (t), 55.1 (q), 65.7 (d),
66.3 (d), 66.4 (t), 70.4 (d), 72.6 (t), 100.3 (q), 113.7 (s),
125.7 (d), 128.3 (d), 128.4 (d), 129.2 (d), 130.6 (d), 135.9
(d), 141.9 (s), 159.1 (s). Anal. Calcd for C34H52O5Si: C,
71.79; H, 9.21. Found: C, 71.93; H, 9.47.
6. Barton, D. H. R.; McCombie, W. W. J. Chem. Soc.,
Perkin Trans. 1 1975, 1574–1585.
25
7. (a) Spectral data of compound 5: mp = 71–72 °C. ½aꢀD À7.7
1
(c 1.1, CHCl3). H NMR (300 MHz, CDCl3) d: 7.30–7.19
(m, 5H), 5.83 (d, J = 3.7 Hz, 1H), 4.72 (br dd, J = 5.0,
3.7 Hz, 1H), 4.26–4.17 (m, 1H), 2.79 (ddd, J = 13.8, 10.3,
5.8 Hz, 1H), 2.69 (ddd, J = 13.8, 9.7, 6.7 Hz, 1H), 2.09 (dd,
J = 13.2, 4.1 Hz, 1H), 2.01–1.77 (m, 2H), 1.50–1.43 (m,
1H), 1.49 (s, 3H), 1.32 (s, 3H). 13C NMR (50 MHz,
CDCl3) d: 26.1 (q), 26.5 (q), 32.3 (t), 35.9 (t), 38.8 (t), 77.1
(d), 80.5 (d), 105.2 (s), 110.7 (s), 125.8 (d), 128.3 (d), 141.0
(s). Anal. Calcd for C15H20O3: C, 72.55; H, 8.12. Found:
C, 72.23; H, 7.95; (b) Spectral data of compound 3:
15. (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett.
1990, 31, 945–948; (b) Evans, D. A.; Rieger, D. L.; Gage,
J. R. Tetrahedron Lett. 1990, 31, 7099–7100.
16. Ando, K. J. Org. Chem. 1997, 62, 1934–1939.
25
17. Spectral data of compound 16: ½aꢀD +16 (c 2.0, CHCl3). 1H
25
NMR (500 MHz, CDCl3) d: 7.28–7.25 (m, 2H), 7.19–7.15
(m, 3H), 6.28 (dt, J = 11.5, 7.2 Hz, 1H), 5.80 (dt, J = 11.5,
1.3 Hz, 1H), 5.58 (dt, J = 15.4, 6.8 Hz, 1H), 5.48 (dd,
J = 15.4, 6.2 Hz, 1H), 4.23 (br q, J = 5.9 Hz, 1H), 4.15 (q,
J = 7.2 Hz, 2H), 3.8 (br tt, J = 8.2, 6.8 Hz, 1H), 3.76–3.71
(m, 1H), 2.85–2.82 (m, 2H), 2.75 (ddd, J = 13.8, 9.3,
5.3 Hz, 1H), 2.61 (ddd, J = 13.8, 9.1, 7.2 Hz, 1H), 2.22 (dt,
J = 13.7, 6.8 Hz, 1H), 2.12 (dt, J = 13.7, 6.6 Hz, 1H), 1.86–
1.79 (m, 1H), 1.74–1.67 (m, 1H), 1.59–1.55 (m, 2H), 1.35
(s, 3H), 1.32 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H), 0.87 (s, 9H),
0.03 (s, 3H), 0.01 (s, 3H). 13C NMR (125 MHz, CDCl3) d:
À4.8 (q), À4.4 (q), 14.3 (q), 18.2 (s), 24.9 (q), 24.9 (q), 25.8
(q), 31.6 (t), 37.5 (t), 37.5 (t), 38.1 (t), 38.5 (t), 59.8 (t), 65.8
(d), 66.3 (d), 72.3 (d), 100.3 (s), 120.8 (d), 125.7 (d), 126.2
(d), 128.3 (d), 128.4 (d), 135.1 (d), 141.9 (s), 146.3 (d),
166.4 (s). Anal. Calcd for C30H48O5Si: C, 69.72; H, 9.36.
Found: C, 69.87; H, 9.49.
½aꢀD À12.7 (c 1, CHCl3). IR: 3109, 1714, 1602, 1275,
756 cmÀ1 1H NMR (500 MHz, CDCl3) d: 8.05 (br dd,
.
J = 7.8, 1.4 Hz, 2H), 7.57 (br tt, J = 7.4, 1.4 Hz, 1H), 7.46
(br d, J = 7.8, 1H), 7.45 (br d, J = 7.8, 1H), 7.27–7.24 (m,
2H), 7.18–7.15 (m, 3H), 5.37 (tt, J = 7.7, 4.8 Hz, 1H),
3.03–3.0 (m, 1H), 2.75 (ddd, J = 13.8, 10.0, 5.8 Hz, 1H),
2.72 (br dd, J = 5.0, 4.0 Hz, 1H), 2.60 (ddd, J = 13.7, 9.9,
6.7 Hz, 1H), 2.46 (dd, J = 5.0, 2.7 Hz, 1H), 2.16–2.03 (m,
2H), 1.98–1.88 (m, 2H). 13C NMR (125 MHz, CDCl3) d:
31.7 (t), 36.2 (t), 37.8 (t), 46.8 (t), 49.1 (d), 72.0 (d), 125.9
(d), 128.3 (d), 128.3 (d), 128.4 (d), 129.5 (d), 130.2 (d),
132.9 (q), 141.1 (q), 165.9 (q). Anal. Calcd for C19H20O3:
C, 77.00; H, 6.80. Found: C, 76.84; H, 7.02.
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