Stereoselective total synthesis of cryptopyranmoscatone A1

Article abstract of DOI:10.1016/j.tetlet.2011.02.107

The first total synthesis of cryptopyranmoscatone A1 isolated from Cryptocarya moschata has been accomplished from 3,4,6-tri-O-acetyl-d-glucal. In addition to the RCM and cross-metathesis (CM) reactions, the synthesis features a highly diastereoselective

Full text of DOI:10.1016/j.tetlet.2011.02.107

Tetrahedron Letters 52 (2011) 2407–2409
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Stereoselective total synthesis of cryptopyranmoscatone A1
⇑
Gowravaram Sabitha , S. Siva Sankara Reddy, J. S. Yadav
Organic Division I, Indian Institute of Chemical Technology (CSIR), Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total synthesis of cryptopyranmoscatone A1 isolated from Cryptocarya moschata has been
Received 29 December 2010
Revised 22 February 2011
Accepted 27 February 2011
Available online 2 March 2011
accomplished from 3,4,6-tri-O-acetyl-D-glucal. In addition to the RCM and cross-metathesis (CM) reac-
tions, the synthesis features a highly diastereoselective Brown’s allylation reaction and sets the absolute
stereochemistry of the natural product.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Cryptopyranmoscatone
oxa-Michael
3,4,6-Tri-O-acetyl-
Cross-metathesis
Brown’s allylation
RCM
D-glucal
Cryptopyranmoscatones A1, A2, A3, B1, B2, and B4 (1–6), gonio-
thalamin (7), and cryptofolione (8) (Fig. 1) are a group of -pyrones
Retrosynthetic analysis is depicted in Scheme 1. We envisaged
that the target molecule 1 can be accomplished through RCM
and cross-metathesis reactions of tetrasubstituted pyran 9 and
pyran 9 could be prepared from derivative 10 by Brown’s asym-
metric allylation. The ester 10 is accessible from 11 by utilizing
oxa-Michael addition reaction, whereas the lactone intermediate
a
isolated from the branch and stem bark of Cryptocarya moschata,
Lauraceae, by Cavalheiro et al.1 The common feature of these
pyrones is that they all contain a styryl group; however, they have
varying carbon skeletons. The structures of these compounds were
established by spectroscopic studies. Cryptocarya species showed
outstanding equipotent activity toward COX-1 and COX-2.2 Some
of the Cryptocarya pyrones have been identified as highly effica-
cious inhibitors of the G2 check point, which can enhance killing
of cancer cells by ionizing radiation and DNA-damaging chemo-
therapeutic agents, particularly in cells lacking p53 function.3
The highly unique structures and the impressive levels of biologi-
cal activities make them as attractive targets for total synthesis.
Earlier, we have reported the synthesis of goniothalamin4a,b and
cryptofolione.4b Quite recently, the first synthesis of cryptopyran-
moscatone B1 (4) was reported by our group,5 where we have
demonstrated tandem stereoselective oxocarbenium cation forma-
tion/reduction reaction to get the 2,6-syn tetrahydropyran (THP)
ring with the required allyl side chain. Now, we herein report the
first total synthesis of cryptopyranmoscatone A1 (1) from 3,4,6-
11 could be made from 3,4,6-tri-O-acetyl-D-glucal 12 by functional
group manipulations.
The synthesis of cryptopyranmoscatone A1 1 was started from
the commercially available tri-O-acetyl- -glucal 12 by selective
D
silylation at position 6, followed by MOM protection at position
3 and position 4, removal of the silyl protecting group, converting
into alkene, subsequent PCC oxidation as reported in our earlier
report5 to obtain lactone 11. The lactone 11 was reduced to lactol
using DIBAL-H and subjected to Wittig olefination using stabilized
ylide to furnish
a,b-unsaturated ester 13 in 85% overall yield
(Scheme 2). The hydroxy ester 13 on exposure to t-BuOK in THF
at ꢀ78 °C readily underwent intramolecular oxa-Michael reaction6
to afford 2,6-trans tetrahydropyran 10 as a single diastereomer
(>20:1) in 95% yield.
The structure of compound 10 was characterized by NMR
experiments including 2-D nuclear Overhauser enhance
spectroscopy (NOESY) and double quantum filtered correlation
spectroscopy (DQFCOSY). From the one dimensional 1H NMR
experiments, 3JH1(Pro-R)-H2 = 8.6, 3JH1(Pro-S)-H2 = 5.6, 3JH2-H3(Pro-R) = 4.0,
tri-O-acetyl-D-glucal by using oxa-Michael addition reaction as
the key step to achieve the 2,6-anti THP ring in addition to the
RCM and CM reactions in combination with Brown’s asymmetric
allylation.
3
3
3
3JH2-H3(Pro-S) = 7.3, JH3(Pro-R)-H4 = 4.0, JH3(Pro-S)-H4 = 6.5, JH4-H5 = 5.4,
3JH5-H6 = 5.4, JH6-H7 = 6.2, JH7-H8 = 10.5 and JH7-H8 = 17.2 Hz, were
determined. By NOESY cross peaks H1(Pro-R)/H3(Pro-S), H1(Pro-S)/
H3(Pro-S), H1(Pro-S)/H6, H1(Pro-R)/H6, H1(Pro-R)/H4, H1(Pro-S)/
3
3
3
⇑
Corresponding author. Tel.: +91 40 27191629; fax: +91 40 27160512.
E-mail address: gowravaramsr@yahoo.com (G. Sabitha).
Visiting Professor, KingSaud University, PO Box 2455, Riyadh 11451, Saudi Arabia.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.107

2408
G. Sabitha et al. / Tetrahedron Letters 52 (2011) 2407–2409
R2
R2
O
O
O
O
OH
O
R1
R1
HO
O
O
O
O
cryptopyranmoscatone B1 (4)
OH ; OH
cryptopyranmoscatone B2 (5)
cryptopyranmoscatone A1 (1)
cryptopyranmoscatone A2 (2)
OH
cryptopyranmoscatone A3 (3)
OH
R1 = R2 =
R1 =
R2 =
R1 = R2 =
R1 =
R2 =
OH ;
OH
O
OH
O
O
HO
O
O
O
OH OH
O
cryptopyranmoscatone B4 (6)
cryptofolione (8)
goniothalamin (7)
Figure 1. Styryl lactones.
H4, H5/H7, and H4/H6, along with the couplings support the en-
ergy minimized structure shown in Figure 2.
O
OMOM
O
OH
O
HO
MOMO
O
O
Reduction of ester group in compound 10 with DIBAL-H in
CH2Cl2 at 0 °C gave alcohol 14 in 84% yield (Scheme 2). Alcohol
14 was oxidized using IBX followed by Brown’s asymmetric
allylation7 with B-allyldiisopinocampheylborane to furnish the
homoallyl alcohol (15, 91% de) in 82% overall yield for the two
step-sequence. The homoallyl alcohol was converted into its acry-
loyl ester 9 and subsequent ring closing metathesis (RCM)8 using
the first-generation Grubbs’ catalyst that yielded lactone 16
exclusively. The cross-metathesis reaction of olefin 16 with styrene
17 using Grubbs’ second generation carbene catalyst9 in benzene at
55 °C for 8 h afforded 18. Finally, cleavage of MOM groups using
4 N HCl in CH3CN/H2O (4:1) at 0 °C for 3 h furnished the target
lactone, cryptopyranmoscatone A1 (1) in 80% yield. The spectral
O
9
cryptopyranmoscatone A1 (1)
OAc
OMOM
OMOM
O
AcO
AcO
MOMO
MOMO
CO2Et
O
O
O
12
11
10
Scheme 1. Retrosynthetic analysis for cryptopyranmoscatone A1.
OMOM
OMOM
OAc
O
OMOM
MOMO
AcO
AcO
MOMO
MOMO
a
b
ref 5
CO2Et
O
O
O
OH
3,4,6-tri-O-acetyl-D
glucal 12
CO2Et
10
13
11
OMOM
O
OMOM
OMOM
MOMO
MOMO
MOMO
c
d
e
OH
O
CH2OH
O
O
O
14
15
9
O
O
OMOM
O
OMOM
MOMO
f
MOMO
h
17
O
1
g
O
O
16
18
Grubbs' II catalyst
Grubbs' I catalyst
Scheme 2. Reagents and conditions: (a) (i) Dibal-H, CH2Cl2, 0 °C, 1 h; (ii) Ph3P@CHCOO2Et, C6H6, reflux, 4 h, 85% (over two steps); (b) t-BuOK (1.1 equiv), THF, ꢀ78 °C, 0.5 h,
95% (20:1 dr); (c) Dibal-H, CH2Cl2, 0 °C, 1 h, 84%; (d) (i) IBX, DMSO, CH2Cl2, 0 °C to rt, 4 h; (ii) (+)-IPC2B(allyl) 1.0 M in pentane, ether, ꢀ100 to 0 °C, 2 h, 82% (over two steps),
(91% de); (e) acryloyl chloride, Et3N, CH2Cl2, 0 °C, 0.5 h, 85%; (f) Grubbs’ 1st generation catalyst (10 mol%), CH2Cl2, reflux, 6 h, 91%; (g) Grubbs’ 2nd generation catalyst
(10 mol%), C6H6, 55 °C, 8 h, 87%; (h) 4 N HCl, CH3CN:H2O (4:1), 0 °C, 3 h, 80%.

G. Sabitha et al. / Tetrahedron Letters 52 (2011) 2407–2409
2409
7. (a) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092; (b) Brown, H. C.;
Bhat, K. S.; Randad, R. S. J. Org. Chem. 1989, 54, 1570; (c) Bolshakov, S.; Leighton,
J. L. Org. Lett. 2005, 7, 3809; (d) Chan, K.-P.; Ling, Y. H.; Loh, T.-P. Chem. Commun.
2007, 939.
8. (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446; (b) Furstner,
A. Angew. Chem., Int. Ed. 2000, 39, 3012; (c) Trnka, T. M.; Grubbs, R. H. Acc.
Chem. Res. 2001, 34, 18; (d) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
9. (a) Scholl, M.; Ding, S.; lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953; (b)
Chatterjee, A. K.; Tae-Lim Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem.
Soc. 2003, 125, 11360.
OMOM
O
MOMO
CO2Et
10. Ethyl 2-[(2S,4R,5R,6R)-4,5-di(methoxymethoxy)-6-vinyltetrahydro-2H-2-pyranyl]-
acetate (10): To a solution of alcohol 13 (1.0 g, 3.14 mmol) in THF (10 mL)
at ꢀ78 °C was added t-BuOK (387 mg, 3.44 mmol). After 0.5 h stirring at
ꢀ78 °C, a saturated solution of NH4Cl (5 mL) was added and the mixture
warmed up to rt. Extraction was carried out with Et2O (3 ꢁ 10 mL). The organic
phase was dried over MgSO4, filtered, and concentrated in vacuo. The
purification of the residue by flash column chromatography (eluent:PE–
EtOAc, 8:2) furnished cycloadduct 10 in 95% yield (950 mg) as a colorless oil.
Figure 2. Energy minimized structure and chemical structure of 10.
Rf = 0.6 (PE–EtOAc, 8:2); ½a D25
ꢂ
: +48 (c = 0.0125 g/mL, CHCl3); 1H NMR (CDCl3,
(IR, 1H, 13C NMR, and mass) data10 of 1 were found to be identical
in all respects with those reported by Cavalheiro et al. for the nat-
ural product1 thereby confirming its structure and absolute
stereochemistry.
In conclusion, we have accomplished the first stereoselective
total synthesis of cryptopyranmoscatone A1 starting from rela-
300 MHz): d 6.09–5.95 (m, 1H), 5.32 (dt, J = 17.3, 1.5 Hz, 1H), 5.19 (dt, J = 10.5,
1.5 Hz, 1H), 4.73–4.59 (m, 4H), 4.47–4.36 (m, 1H), 4.19–4.07 (m, 3H), 3.89–3.79
(m, 1H), 3.44–3.38 (m, 1H), 3.35 (d, J = 3.0 Hz, 6H), 2.64 (dd, J = 15.1, 8.3 Hz,
1H), 2.40 (dd, J = 15.1, 6.0 Hz, 1H), 1.96–1.84 (m, 1H), 1.80–1.69 (m, 1H), 1.26
(t, J = 6.7 Hz, 3H); 13C NMR (CDCl3, 75 MHz): 171, 135.1, 117.3, 96.4, 95.5, 75.9
(d, 2C), 72.8, 65.3, 60.5, 55.9, 55.5, 39.4, 32.7, 14.2; IR (Neat): 2927, 1734, 1644,
1446, 1151, 1034, 921 cmꢀ1; ESIMS: m/z 341 [M+Na]+; HRMS: m/z [M+Na]+
calcd for C15H26O7Na: 341.1576; found: 341.1587; (2R)-1-[(2R,4R,5R,6R)-4,5-
tively cheap and commercially available tri-O-acetyl-D-glucal
di(methoxymethoxy)-6-vinyltetrahydro-2H-2-pyranyl]-4-penten-2-ol (15): ½a D25
ꢂ
:
utilizing Brown’s asymmetric allylation in addition to RCM,
cross-metathesis, and oxa-Michael reactions. This report provides
an attractive method for the preparation of other natural analogs,
which is underway in our lab and the results will be published in
due course.
+45 (c = 0.01 g/mL, CHCl3); 1H NMR (CDCl3, 400 MHz): d 6.15–6.01 (m, 1H),
5.89–5.72 (m, 1H), 5.33 (d, J = 17.3 Hz, 1H), 5.23 (d, J = 10.5 Hz, 1H), 5.12–5.01
(m, 2H), 4.73–4.59 (m, 4H), 4.29–4.13 (m, 2H), 3.91–3.78 (m, 2H), 3.48–3.41
(m, 1H), 3.35 (d, J = 5.2 Hz, 6H), 2.33–2.11 (m, 2H), 1.95–1.60 (m, 2H), 1.54–
1.23 (m, 2H); 13C NMR (CDCl3, 75 MHz): 135.0, 134.8, 117.7, 117.3, 96.3, 95.5,
76.0, 75.5, 72.6, 71.3, 68.9, 55.8, 55.6, 41.8, 39.6, 33.4; IR (Neat): 3450, 2929,
1638, 1438, 1149, 1035, 918 cmꢀ1; ESIMS: m/z 339 [M+Na]+; HRMS: m/z
[M+Na]+ calcd for C16H28O6Na: 339.1783; found: 339.1778; (6R)-6-
[(2S,4R,5R,6R)-4,5-di(methoxymethoxy)-6-vinyltetrahydro-2H-2-pyranyl]methyl-
Acknowledgments
5,6-dihydro-2H-2-pyranone (16): ½a D25
ꢂ
: +91 (c = 0.0115, CHCl3); 1H NMR (CDCl3,
S.S.S. Reddy thanks CSIR, New Delhi for the award of fellowship.
We thank Dr. A.C. Kunwar and P. Purushotham Reddy, NMR Divi-
sion, IICT, Hyderabad for NOE studies.
400 MHz): d 6.88–6.80 (m, 1H), 6.21–6.07 (m, 1H), 5.99 (dt, J = 9.8, 1.5 Hz, 1H),
5.31–5.16 (m, 2H), 4.74–4.53 (m, 5H), 4.23–4.07 (m, 1H), 3.90–3.81 (m, 1H),
3.49–3.31 (m, 8H), 2.47–2.13 (m, 3H), 1.98–1.67 (m, 3H); 13C NMR (CDCl3,
75 MHz): 164.4, 145.2, 135.2, 121.2, 117.8, 96.3, 95.6, 76.3, 75.5, 75.1, 72.6,
63.8, 55.8, 55.6, 38.4, 33.0, 28.7; IR (Neat): 2927, 1721, 1636, 1386, 1249, 1035,
920 cmꢀ1; ESIMS: m/z 365 [M+Na]+; HRMS: m/z [M+Na]+ calcd for C17H26O7Na:
365.1576; found: 365.1576; (6R)-6-((2S,4R,5S,6R)-4,5-dihydroxy-6-[(E)-2-
phenyl-1-ethenyl]tetrahydro-2H-2-pyranylmethyl)-5,6-dihydro-2H-2-pyranone
References and notes
1. Cavalheiro, A. J.; Yoshida, M. Phytochemistry 2000, 53, 811.
(1): ½a 2D5
ꢂ
: +45 (c = 0.0095 g/mL, CHCl3); 1H NMR (CDCl3, 300 MHz): d 7.42–7.20
2. Zschocke, S.; van Staden, J. J. Ethnopharmacol. 2000, 71, 473.
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Andersen, R. J.; Roberge, M. Cancer Chemother. Pharmacol. 2008, 61, 407.
4. (a) Sabitha, G.; Sudhakar, K.; Yadav, J. S. Tetrahedron Lett. 2006, 47, 8599; (b)
Sabitha, G.; Siva Sankara Reddy, S.; Vasudeva Reddy, D.; Bhaskar, V.; Yadav, J. S.
Synthesis 2010, 3453.
5. Sabitha, G.; Siva Sankara Reddy, S.; Yadav, J. S. Tetrahedron Lett. 2010, 51, 6259.
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M.-A.; Pelotier, B.; Piva, O. Tetrahedron Lett. 2010, 51, 5091.
(m, 5H), 6.90–6.82 (m, 1H), 6.68 (d, J = 15.8 Hz, 1H), 6.21 (dd, J = 15.8, 6.9 Hz,
1H), 6.00 (dt, J = 9.8, 1.5 Hz, 1H), 4.59–4.47 (m, 1H), 4.32–4.21 (m, 1H), 4.00 (t,
J = 7.5 Hz, 1H), 3.94–3.84 (m, 1H), 3.32–3.23 (m, 1H), 2.54–2.30 (m, 3H), 2.01–
1.68 (m, 3H); 13C NMR (CDCl3, 75 MHz): 164.5, 145.3, 136.1, 133.7, 128.6,
128.0, 126.6, 126.1, 121.2, 75.9, 75.3, 74.5, 68.9, 68.3, 35.8, 35.6, 28.5; IR (Neat):
3388, 2927, 1707, 1388, 1256, 1056, 816, 749, 694 cmꢀ1; ESIMS: m/z 353
[M+Na]+; HRMS: m/z [M+Na]+ calcd for C19H22O5Na: 353.1364; found:
353.1369.