Total synthesis of cryptopyranmoscatone B1 from 3,4,6-tri-O-acetyl-d-glucal

Article abstract of DOI:10.1016/j.tetlet.2010.09.085

The first stereoselective total synthesis of the natural cryptopyranmoscatone B1 has been accomplished from 3,4,6-tri-O-acetyl-d-glucal. In addition to the double cross-metathesis reaction, a tandem nucleophilic addition-diastereoselective reduction of an

Full text of DOI:10.1016/j.tetlet.2010.09.085

Tetrahedron Letters 51 (2010) 6259–6261
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Tetrahedron Letters
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Total synthesis of cryptopyranmoscatone B1 from 3,4,6-tri-O-acetyl-D-glucal
⇑
Gowravaram Sabitha , S. Siva Sankara Reddy, J. S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The first stereoselective total synthesis of the natural cryptopyranmoscatone B1 has been accomplished
Received 13 August 2010
Revised 14 September 2010
Accepted 18 September 2010
Available online 29 September 2010
from 3,4,6-tri-O-acetyl-D-glucal. In addition to the double cross-metathesis reaction, a tandem nucleo-
philic addition-diastereoselective reduction of an in situ generated oxocarbenium cation have been used
as key steps to assemble the glycoside moiety of the target molecule.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Cryptopyranmoscatone
Styryllactone
3,4,6-Tri-O-acetyl-
Cross-metathesis
b-C-Glycoside
D-glucal
In 2000, Cavalheiro and Yoshida1 reported the isolation of cryp-
topyranmoscatones A1, A2, A3, B1, B2, and B4 (1–6), goniothalamin
(7) and cryptofolione (8) (Fig. 1) from the branch and stem bark of
Cryptocarya moschata, Lauraceae, a tree found in the southeastern
region of Brazil. The structures were established by spectroscopic
lines.2 Some of the Cryptocarya pyrones have been identified as
highly efficacious inhibitors of the G2 check point, particularly in
cells lacking p53 function.3 The highly unique structure and the
impressive levels of biological activities make them as attractive
targets for total synthesis. Earlier, we have reported the synthesis
of goniothalamin4a,b and cryptofolione.4b We report herein the first
total synthesis of cryptopyranmoscatone B1 (4) starting from rela-
studies and these 5,6-dihydro-a-pyrones contain a styryl group at-
tached to the C6 side chain. Styryllactones in general are reported
to possess significant cytotoxicity toward several human tumor
tively inexpensive and commercially available 3,4,6-tri-O-acetyl-D-
OH
O
O
OH
O
O
R
O
O
HO
HO
R1
O
O
O
cryptopyranmoscatone A1 (1)
R =
R1
OH
OH
cryptopyranmoscatone B2 (5)
cryptopyranmoscatone B1 (4)
=
O
O
cryptopyranmoscatone A2 (2) R =
OH
OH
O
OH
O
R1
=
HO
O
cryptopyranmoscatone A3 (3) R =
R1
OH
OH
=
O
goniothalamin (7)
cryptopyranmoscatone B4 (6)
O
OH OH
cryptofolione (8)
Figure 1. 5,6-Dihydro-a-pyrones.
⇑
Corresponding author. Tel.: +91 40 27191629; fax: +91 40 27160512.
E-mail address: gowravaramsr@yahoo.com (G. Sabitha).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.085

6260
G. Sabitha et al. / Tetrahedron Letters 51 (2010) 6259–6261
OMOM
O
O
OH
O
O
MOMO
HO
O
O
+
9
10
cryptopyranmoscatone B1 (4)
OMOM
OAc
OMOM
MOMO
AcO
AcO
MOMO
13
O
O
O
O
O
11
12
14
Scheme 1. Retrosynthetic analysis for cryptopyranmoscatone B1.
glucal, the chiral centers present will perfectly match with the tar-
get molecule. This synthesis will enable us to evaluate the biolog-
ical activity of the target molecule.
Retrosynthetic analysis is depicted in Scheme 1. We anticipated
that the target molecule can be accomplished through a cross-
metathesis reaction of tetrasubstituted pyran 9 with the known vi-
nyl lactone 105 whereas the pyran 9 could be prepared from the
lactone derivative 11 which in turn could be made by cross-
metathesis reaction of the alkene derivative 12 with styrene 13.
The lactone intermediate 12 could be made from 3,4,6-tri-O-acet-
yl-D-glucal 14 by functional group manipulations, one carbon
Wittig reaction and PCC-promoted transformation.
OR
OAc
OH
RO
AcO
AcO
HO
HO
a
b
d
TBDMSO
O
O
O
; R = H
; R = MOM
16
17
3,4,6-tri-O-acetyl-D
glucal 14
c
D-Glucal 15
OMOM
OMOM
OMOM
MOMO
HO
MOMO
MOMO
13
f
e
g
O
O
O
O
18
12
19
OMOM
OMOM
OMOM
MOMO
MOMO
MOMO
h (i
(ii)
)
O
+
O
O
O
OH
21
11
20
O
O
OMOM
O
OMOM
MOMO
j
O
MOMO
4
10
O
i
O
22
9
Grubbs' II catalyst
Scheme 2. Reagents and conditions: (a) Ref. 6; (b) TBDMSCl (1.1 equiv), imidazole, DMF, rt, 8 h, 87% over two steps; (c) MOMCl, Hunigs base, CH2Cl2, 0 °C to rt, 4 h, 92%; (d)
TBAF, THF, rt, 2 h, 70%; (e) (i) IBX, DMSO, DCM, 0 °C to rt, 10 h; (ii) n-BuLi, Ph3PCH3I, THF, À50 °C to rt, 3 h, 75% over two steps; (f) PCC, silica gel, CH2Cl2, 45 °C, 8 h, 83%; (g)
Grubbs’ catalyst II (10 mol %), C6H6, 55 °C, 5 h, 87%; (h) (i) allylMgBr (3 equiv), THF, À78 °C, 1 h, (ii) TFA (4 equiv), Et3SiH (9 equiv), CH2Cl2, À78 °C, 2 h, 68% over two steps; (i)
Grubbs’ catalyst II (7 mol %), CH2Cl2, reflux, 6 h, 87%; (j) 4 N HCl, CH3CN/H2O (4:1), 0 °C to rt, 1 h, 79%.

G. Sabitha et al. / Tetrahedron Letters 51 (2010) 6259–6261
6261
D
-Glucal6 15, was prepared from the commercially available tri-
O-acetyl- -glucal 14 by de-O-acetylation. -Glucal 15 was selec-
tively cheap and commercially available tri-O-acetyl-
D
-glucal uti-
D
D
lizing double cross-metathesis reaction and the construction of
b-C-glycoside subunit by a one-pot oxocarbenium cation forma-
tion/reduction sequence. This Letter provides an attractive method
for the preparation of other natural analogs.
tively silylated at the sixth position to give compound 16, which
was then treated with MOMCl and Hunig’s base in CH2Cl2 affording
fully protected 3,4-di-O-MOM-6-O-silylated-D-glucal derivative 17
(Scheme 2). Removal of the silyl protecting group of 17 with TBAF
provided primary alcohol 18 in 70% yield, which was converted
into alkene 19 by subsequent oxidation using IBX in DMSO/CH2Cl2
Acknowledgment
followed by Wittig reaction. This
D-glucal derivative 19 was sub-
S.S.S. Reddy thanks CSIR, New Delhi for the award of fellowship.
jected to pyridinium chlorochromate (PCC)-promoted transforma-
tion of cyclic enol ether to lactone at 45 °C in the presence of silica
gel to give key intermediate 12 in 83% yield. The cross-metathesis
reaction of olefin 12 with styrene 13 using Grubbs’ second gener-
ation carbene catalyst7 in benzene at 55 °C for 5 h afforded 11.
With the key lactone 11 in hand, our attention was initially focused
on the allyl b-C-glycoside formation followed by final elaboration
of the terminal alkene functional group into the final targeted mol-
ecule 4. Thus, treatment of lactone 11 with excess allylmagnesium
bromide in THF at À78 °C readily afforded the lactol intermediate
20 as a mixture of two diastereomers, which readily underwent
tandem stereoselective oxocarbenium cation formation/reduction
with TFA and Et3SiH to afford the b-C-glycoside 9 in 68% yield from
11 (in >20:1 dr). Presumably, reduction of oxocarbenium cation oc-
curs via axial addition of Et3SiH to afford the glycoside. This
assumption was made based on previous reports.8
The second cross-metathesis reaction of terminal alkene 9 with
the known vinyl lactone 10 using Grubbs’ second generation cata-
lyst in refluxing CH2Cl2 for 7 h furnished the required lactone 22 in
87% yield. Finally, removal of MOM groups using 4 N HCl in CH3CN/
H2O (4:1) at 0 °C for 1 h furnished the target lactone, cryptopyran-
moscatone B1 (4) in 79% yield. The spectra and physical data of the
synthetic 4 are in agreement with those of the natural compound
thereby confirming its structure and absolute stereochemistry.1
In conclusion, we have accomplished the first stereoselective
total synthesis of cryptopyranmoscatone B1 starting from rela-
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.09.085.
References and notes
1. Cavalheiro, A. J.; Yoshida, M. Phytochemistry 2000, 53, 811–819.
2. (a) Fang, X. P.; Anderson, J. E.; Chang, C. J.; McLaughlin, J. L. J. Nat. Prod. 1991, 54,
1034–1043; (b) Fang, X. P.; Anderson, J. E.; Chang, C. J.; McLaughlin, J. L.
Tetrahedron 1991, 47, 9751–9758; (c) Tsubuki, M.; Kanai, K.; Nagase, H.; Honda,
T. Tetrahedron 1999, 55, 2493–2514.
3. Sturgeon, C. M.; Cinel, B.; Diaz-Marrero, A. R.; McHardy, L. M.; Ngo, M.;
Andersen, R. J.; Roberge, M. Cancer Chemother. Pharmacol. 2008, 61, 407–413.
4. Goniothalamin: (a) Sabitha, G.; Sudhakar, K.; Yadav, J. S. Tetrahedron Lett. 2006,
47, 8599–8602; Cryptofolione and goniothalamin (b) Sabitha, G.; Reddy, S. S. S.;
Reddy, D. V.; Bhaskar, V.; Yadav, J. S. Synthesis 2010, 3453–3460.
5. (a) Sabitha, G.; Fatima, N.; Gopal, P.; Reddy, C. N.; Yadav, J. S. Tetrahedron:
Asymmetry 2009, 20, 184–191; (b) Sabitha, G.; Bhaskar, V.; Reddy, S. S. S.; Yadav,
J. S. Helv. Chim. Acta 2010, 93, 329–338; (c) Sabitha, G.; Gopal, P.; Reddy, C. N.;
Yadav, J. S. Tetrahedron Lett. 2009, 50, 6298–6302.
6. Although
D-glucal is commercially available, tri-O-acetyl-D-glucal is much
cheaper and can be used for large-scale synthesis: Fetizon, M.; Khac, D. D.;
Tho, D. N. Tetrahedron Lett. 1986, 27, 1777–1780.
7. (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, 11360–11370.
8. (a) Carrick, J. D.; Jennings, M. P. Org. Lett. 2009, 11, 769–772; (b) Martinez-
Solorio, D.; Jennings, M. P. J. Org. Chem. 2010, 75, 4095–4104; (c) Sawant, K. B.;
Ding, F.; Jennings, M. P. Tetrahedron Lett. 2006, 47, 939–942.