A [2+2+2]-cyclotrimerization approach for the synthesis of enantiopure isochromans using a carbohydrate derived dialkyne template

Article abstract of DOI:10.1016/j.tetlet.2007.11.103

An easy access to enantiopure isochromans through cross alkyne trimerization of a glucose derived dialkyne was developed. One of the synthesized isochromans was converted into a novel tricyclic nucleoside by simple transformations.

Full text of DOI:10.1016/j.tetlet.2007.11.103

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 445–448
A [2+2+2]-cyclotrimerization approach for the synthesis of enantiopure
isochromans using a carbohydrate derived dialkyne template
C. V. Ramana *, Sharad B. Suryawanshi
National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
Received 1 October 2007; revised 16 November 2007; accepted 20 November 2007
Available online 23 November 2007
Abstract
An easy access to enantiopure isochromans through cross alkyne trimerization of a glucose derived dialkyne was developed. One of
the synthesized isochromans was converted into a novel tricyclic nucleoside by simple transformations.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Isochroman; [2+2+2]-Cyclotrimerization; Wilkinson’s catalyst; Vorbruggen reaction; Tricyclic nucleoside
¨
Designing effective routes to construct complex cyclic
structures through organo transition-metal catalyzed reac-
O
R
tions has been recognized as an attractive strategy for
R''
delivering molecular diversity.1 Integrated with transition-
O
O
O
R'
metal catalyzed reactions, sugar templates have been well
Investigational
herbicide (2)
isochroman (1)
deployed to address the synthesis of a variety of complex
natural product skeletons.2 Amongst the many other metal
O
O
catalyzed reactions which have been explored on sugar
templates, catalytic [2+2+2]-alkyne cyclotrimerizations
+
R
R
O
O
are important as they deliver highly functionalized aro-
matic rings appended with sugar rings.3 An early example
O
in this context is an expedient total synthesis of the spiro-
O
cyclic C-arylglycoside framework closely related to the
papulacandins by McDonald et al. utilizing a rhodium(I)-
O
O
key diyne 3
catalyzed [2+2+2]-cyclotrimerization4 which has been well
explored with various sugar derivatives.5 Considering the
simplicity of the [2+2+2]-alkyne cyclotrimerization com-
bined with our current interest in exploiting carbohydrates
for constructing useful molecular diversity,6 herein, we
report the synthesis of enantiomeric tricyclic molecular
skeletons consisting of isochroman units (Fig. 1).
Fig. 1. Key [2+2+2]-cyclotrimerization approach for enantiopure iso-
chromans.
compounds, commercially available drugs and cosmetics.7
Several synthetic 6,7-dimethoxyisochromans and their
1-arylated analogues have been disclosed as new investi-
gational drugs with a wide range of activities such as
analgesic, muscle relaxant, antidepressant, anti-inflamma-
tory, antihistaminic, anticoagulant and antihypertensive.8
Kakimoto et al. prepared a series of tricyclic isochroman
derivatives 2 from glucose and evaluated their herbicidal
Isochroman (1, 3,4-dihydro-1H-benzo[c]pyran) is a
structural unit found in some important biologically active
*
Corresponding author. Tel.: +91 20 25902577; fax: +91 20 25902629.
E-mail address: vr.chepuri@ncl.res.in (C. V. Ramana).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.103

446
C. V. Ramana, S. B. Suryawanshi / Tetrahedron Letters 49 (2008) 445–448
activities.9 A number of synthetic methods involving elec-
trophilic reactions mediated by Lewis acids, radical and
carbanion-mediated annulations, and cycloadditions have
been reported for the synthesis of isochroman units.7 The
oxa-Pictet–Spengler condensation is a widely used method
for the preparation of isochroman units.7b An expedient
approach for sugar annulated isochromans by Martin
et al. using intramolecular Friedel–Crafts cyclization has
been reported.10 Recently, Kaliappan and Ravikumar
reported an intramolecular enyne-metathesis and subse-
quent trapping of the resulting dienes by various quinones
for the synthesis of tetracyclic derivatives containing an
isochroman ring.11
Our intended strategy is described in Figure 1. The syn-
thesis of the key diyne 3 started with the propargylation of
glucose diacetonide 4 to procure the propargyl ether 5.12
Selective monoacetonide hydrolysis of 5 followed by
sodium periodate mediated cleavage and subsequent
Ohira–Bestmann alkynylation13 of the intermediate alde-
hyde provided 3 in 49% overall yield (Scheme 1). With
the fully elaborated diyne framework 3 in place, cyclotri-
merization was attempted with 2-butyne-1,4-diol (6). After
a careful examination of some of the catalysts reported for
O
O
O
O
O
O
O
O
a
O
O
O
O
HO
5
4
OH
b
O
O
c
HO
O
O
O
O
O
HO
OH
7
3
6
Scheme 1. Reagents and conditions: (a) NaH, propargyl bromide, THF,
0 °C to rt, 8 h, 89%; (b) (i) 0.8% H2SO4, MeOH, rt, 24 h; (ii) NaIO4–silica
gel, CH2Cl2, rt, 1 h; (iii) (MeO)2P(@O)C(@N2)COCH3, methanol, K2CO3,
rt, 7–9 h, 49% for three steps; (c) Rh(PPh3)2Cl, toluene–ethanol (4:1),
80 °C, 8 h, 61%.
[2+2+2]-alkyne cyclotrimerization, we found that Wilkin-
son’s catalyst afforded the tricyclic derivative 7 in good
yields.5d The spectral and analytical data of 7 were in
accordance with the assigned structure.14 For example, in
the 1H NMR spectrum of 7, the two aromatic-H appeared
Table 1
Entry
Alkyne
Yield (%)
Product(s)
R'
R
O
O
O
O
1
2
7 (R = R0 = CH2OH)
8 (R = R = H)
61
65
HO
H
OH
H
3
4
9 (R = R0 = CH2Oac)
10 (R = R0 = CO2Me)
57
45
AcO
OAc
CO2Me
TMS
Ph
MeO2C
5
6
7
No reaction
No reaction
No reaction
TMS
Ph
n-C5H11
n-C5H11
8
9
11 (R = Ph, R0 = H)
12 (R = H, R0 = Ph)
(1:3)
72
67
Ph
H
O
13 (R = CH2NPhth, R0 = H)
14 (R = H, R0 = CH2NPhth)
(2:3)
N
O
10
15 (R = n-C14H29, R0 = H)
49
n
-C14H29
H
16 (R = H, R0 = n-C14H29
)
(1:1)

C. V. Ramana, S. B. Suryawanshi / Tetrahedron Letters 49 (2008) 445–448
447
as singlets at d 6.99 and d 7.24 ppm. The characteristic
C(1)–H and C(2)–H of the furanose ring appeared as dou-
blets at d 5.92 and 4.70 ppm (J1,2 = 3.8 Hz), respectively.
C(4)–H appeared downfield (d 4.89 ppm) as a doublet with
J = 2.3 Hz. The observed cross peaks in the NOESY spec-
trum between C(4)–H and the aromatic ring proton at d
7.24 ppm were indicative of a possible anisotropic effect
of the furanose ring oxygen, which helped in assigning
the ratios of the regiomeric compounds resulting from
unsymmetric alkynes. The presence of two methyleneoxy
groups at d 62.7 and 66.9 ppm in the 13C NMR further
confirmed the assigned structure.
formationally restricted nucleosides as antiviral agents
and as potential antisense therapeutic and diagnostic
agents, the results from the present investigation could be
further explored for a strategic construction of these
molecular skeletons. Work in this direction is ongoing in
our laboratory.
Acknowledgements
We thank the Director (NCL) for the constant encour-
agement and SBS thanks CSIR (New Delhi) for financial
assistance in the form of a research fellowship.
To illustrate the flexibility of our strategy, various
alkynes were employed in the [2+2+2]-cyclotrimerization
and the results are summarized in Table 1. With acetylene,
the cyclotrimerization reaction proceeded effectively at
80 °C in a sealed tube to afford 8 in good yield.15 Unsym-
metrical alkynes such as phenylacetylene and hexadec-1-
yne gave inseparable regiomeric mixtures in moderate to
good yields (Table 1).
References and notes
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4. McDonald, F. E.; Zhu, H. Y. H.; Holmquist, C. R. J. Am. Chem. Soc.
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Having established the feasibility of the [2+2+2]-cyclo-
trimerization for the synthesis of sugar annulated isochro-
mans, we next applied isochroman 8 for the synthesis of
modified nucleoside 19. As shown in Scheme 2, isochroman
8 was subjected to acid catalyzed acetonide hydrolysis
using acetic acid followed by acetylation in dichlorometh-
ane, acetic anhydride and Et3N to afford a 1:1 anomeric
mixture of 17. Treatment of 17 with uracil under modified
Vorbruggen16 conditions afforded the protected nucleoside
¨
18.17 Subjecting 18 to Zemplen’s deacetylation gave the tri-
cyclic nucleoside 19. The structure of 1918 was established
with the help of COSY and NOESY spectra that confirmed
the assigned b-configuration for 19 beyond doubt.
´
´
To conclude, a general synthesis of chiral isochromans
via [2+2+2]-cyclotrimerization of a sugar template as the
key reaction was reported. One of the derived isochromans
was converted into a tricyclic nucleoside by simple syn-
thetic manipulations. Considering the importance of con-
6. (a) Gurjar, M. K.; Nayak, S.; Ramana, C. V. Tetrahedron Lett. 2005,
46, 1881–1884; (b) Ramana, C. V.; Mallik, R.; Gonnade, R. G.;
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479–493; (b) Larghi, E. L.; Kaufman, T. S. Synthesis 2006, 187–220;
(c) Arimitsu, S.; Hammond, G. B. J. Org. Chem. 2006, 71, 8665–
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8. (a) McCall, J. M.; McCall, R. B.; TenBrink, R. E.; Kamdar, B. V.;
Humphrey, S. J.; Sethy, V. H.; Harris, D. W.; Daenzer, C. J. Med.
Chem. 1982, 25, 75–81; (b) TenBrink, R. E.; Bergh, C. L.; Duncan, J.
N.; Harris, D. W.; Huff, R. M.; Lahti, R. A.; Lawson, C. F.; Lutzke,
B. S.; Martin, I. J.; Rees, S. A.; Schlachter, S. K.; Sih, J. C.; Smith, M.
W. J. Med. Chem. 1996, 39, 2435–2437; (c) Unterhalt, B.; Jo¨sting-
meier, R.; Sanatgar, A. Pharmazie 1997, 52, 186–189; (d) Bury, P. S.;
Christiansen, L. B.; Jacobsen, P.; Jorgensen, A. S.; Kanstrup, A.;
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Korsgaard, N.; Thorpe, S. M.; Wassermann, K. Bioorg. Med. Chem.
2002, 10, 125–145; (e) Liu, J.; Birzin, E. T.; Chan, W.; Yang, Y. T.;
Pai, L.-Y.; DaSilva, C.; Hayes, E. C.; Mosley, R. T.; DiNinno, F.;
Rohrer, S. P.; Schaeffer, J. M.; Hammond, M. L. Bioorg. Med. Chem.
Lett. 2005, 15, 715–718; (f) Suzuki, T.; Tanemura, K.; Horaguchi, T.;
Kaneko, K. Tetrahedron 2006, 62, 3739–3751; (g) Mohr, P.; Decker,
O
O
OAc
OAc
O
a
O
O
b
O
17
8
O
O
NH
NH
N
N
O
O
c
O
O
O
O
OH
OAc
19
18
Scheme 2. Reagents and conditions: (a) (i) 60% AcOH, reflux, 2 h, 92%;
(ii) Ac2O, Et3N, DMAP, CH2Cl2, rt, 1 h, 94%; (b) uracil, N,O-
bis(trimethylsilyl)acetamide (BSA), TMSOTf, CH3CN, 50 °C, 2 h, 79%;
(c) NaOMe, MeOH, rt, 20 min, 96%.

448
C. V. Ramana, S. B. Suryawanshi / Tetrahedron Letters 49 (2008) 445–448
M.; Enzensperger, C.; Lehmann, J. J. Med. Chem. 2006, 49, 2110–
2116.
128.7 (d), 129.5 (s), 130.7 (d), 134.8 (s) ppm. ESI-MS: m/z 266.32
(35.9%, [M+NH4]+), 271.29 (100%, [M+Na]+). Anal. Calcd for
9. Kakimoto, T.; Koizumi, F.; Hirase, K.; Banba, S.; Tanaka, E.; Arai,
K. Pest Manag. Sci. 2004, 60, 493–500.
C
14H16O4: C, 67.73; H, 6.50. Found: C, 67.44; H, 6.89.
16. (a) Niedballa, U.; Vorbru¨ggen, H. J. Org. Chem. 1974, 39, 3654–3660;
(b) Vorbruggen, H.; Krolikewiez, K.; Bennua, B. Chem. Ber. 1981,
10. (a) Martin, O. R. Carbohydr. Res. 1987, 171, 211–222; (b) Martin, O.
R.; Hendricks, C. A. V.; Deshpande, P. P.; Cutler, A. B.; Kane, S. A.;
Rao, S. P. Carbohydr. Res. 1990, 196, 41–58; (c) Kulkarni, S. S.; Liu,
Y.-H.; Hung, S.-C. J. Org. Chem. 2005, 70, 2808–2811.
11. Kaliappan, K. P.; Ravikumar, V. Org. Biomol. Chem. 2005, 3,
848–851.
¨
114, 1234–1255; (c) Vorbruggen, H.; Ho¨fle, G. Chem. Ber. 1981, 114,
1256–1268.
¨
25
17. Spectral data of compound 18: ½aꢀD ꢁ8.6 (c 1.0, CHCl3). IR (CHCl3) m:
3032, 2927, 1750, 1682, 1461, 1371, 1320, 1268, 1225, 1108, 1066, 909,
78, 761, 734, 667, 602 cmꢁ1 1H NMR (200 MHz, CDCl3) d: 2.17 (s,
.
12. (a) Rochet, P.; Vatele, J.-M.; Gore, J. Synthesis 1994, 795–799; (b)
Roy, A.; Sahabuddin, S. K.; Achari, B.; Mandal, S. B. Tetrahedron
2005, 61, 365–371.
3H), 4.18 (d, J = 2.6 Hz, 1H), 4.71 (d, J = 15.16 Hz, 1H), 4.86 (d,
J = 15.16 Hz, 1H), 4.95 (d, J = 2.5 Hz, 1H), 5.22 (d, J = 1.6 Hz, 1H),
5.60 (dd, J = 2.1, 8.2 Hz, 1H), 6.15 (d, J = 1.6 Hz, 1H), 7.11 (dd,
J = 2.1, 8.2 Hz, 1H), 7.32–7.48 (m, 4H), 9.21 (br s, 1H). 13C NMR
(50 MHz, CDCl3) d: 20.7 (q), 67.3 (t), 75.4 (d), 78.8 (d), 81.7 (d), 89.3
(d), 102.5 (d), 124.4 (d), 127.82 (d), 127.9 (s), 129.4 (d), 130.6 (d),
134.1 (s), 140.5 (d), 150.2 (s), 163.1 (s), 169.2 (s) ppm. ESI-MS: m/z
344.09 (5.11%, [M]+), 367.02 (100%, [M+Na]+). Anal. Calcd for
C17H16N2O6: C, 59.30; H, 4.68; N, 8.14. Found: C, 59.03; H, 4.90; N,
7.97.
13. (a) Ohira, S. Synth. Commun. 1989, 19, 561–564; (b) Roth, G. J.;
Liepold, B.; Mu¨ller, S. G.; Bestmann, H. J. Synlett 1996, 521–522.
25
14. Spectral data of compound 7: ½aꢀD 28:0 (c 1.2, CHCl3). IR (CHCl3) m:
3401, 3016, 2933, 1734, 1513, 1452, 1438, 1376, 1247, 1216, 1163,
1118, 1102, 1080, 1017, 898, 857, 830, 755, 667 cmꢁ1 1H NMR
.
(200 MHz, CDCl3) d: 1.35 (s, 3H), 1.58 (s, 3H), 3.90 (br s, 2H), 4.09
(d, J = 2.3 Hz, 1H), 4.47–4.60 (m, 5H), 4.67 (d, J = 3.8 Hz, 1H), 4.70
(d, J = 15.1 Hz, 1H), 4.89 (d, J = 2.3 Hz, 1H), 5.92 (d, J = 3.8 Hz, 1H
), 6.99 (s, 1H), 7.24 (s, 1H). 13C NMR (50 MHz, CDCl3) d: 26.1 (q),
26.7 (q), 62.7 (t), 66.9 (t), 73.1 (d), 79.8 (d), 84.4 (d), 104.9 (d), 111.7
(s), 124.6 (d), 128.4 (s), 130.9 (d), 132.1 (d), 134.4 (s), 138.2 (s), 140.2
(s) ppm. ESI-MS m/z: 301.26 (100%), 309.36 (2.3%, [M+1]+), 331.32
(89.2%, [M+Na]+), 347.30 (3.5%, [M+K]+). Anal. Calcd for
C16H20O6: C, 62.33; H, 6.54. Found: C, 62.12; H, 6.68.
25
18. Spectral data of compound 19: ½aꢀD 60:4 (c 1.9, CHCl3). IR (CHCl3) m:
3383, 3218, 3108, 3068, 2923, 2844, 2252, 1775, 1695, 1493, 1464,
1408, 1393, 1373, 1360, 1322, 1265, 1206, 1114, 1097, 1076, 1059, 999,
1
960, 908, 877, 813, 788, 733, 649 cmꢁ1. H NMR (200 MHz, CDCl3)
d: 4.22 (d, J = 1.9 Hz, 1H), 4.52 (s, 1H), 4.64 (d, J = 15.1 Hz, 1H),
4.72 (d, J = 15.1 Hz, 1H), 5.24 (d, J = 1.9 Hz, 1H), 5.48 (d,
J = 8.0 Hz, 1H), 5.65 (s, 1H), 5.89 (s, 1H), 7.1 (dd, J = 2.3, 8.1 Hz,
1H), 7.15 (d, J = 8.03 Hz, 1H), 7.34–7.36 (m, 2H), 7.46 (dd, J = 2.3,
8.1 Hz, 1H), 10.61 (br s, 1H). 13C NMR (50 MHz, CDCl3) d: 66.9 (t),
77.1 (d), 80.1 (d), 80.7 (d), 94.2 (d), 101.1 (d), 124.3 (d), 127.8 (d),
128.8 (s), 129.2 (d), 130.8 (d), 134.3 (s), 140.7 (d), 151.1 (s), 164.2 (s)
ppm. ESI-MS: m/z 325.01 (100%, [M+Na]+), 340.99 (7.3%, [M+K]+).
Anal. Calcd for C15H14N2O5: C, 59.60; H, 4.67; N, 9.27. Found: C,
59.33; H, 4.92; N, 8.99.
25
15. Spectral data of compound 8: ½aꢀD 21:6 (c 1.5, CHCl3). IR (CHCl3) m:
3018, 2927, 1458, 1376, 1216, 1164, 1116, 1091, 1020, 920, 754,
666 cmꢁ1 1H NMR (200 MHz, CDCl3): d 1.28 (s, 3H), 1.50 (s, 3H),
.
4.06 (d, J = 2.4 Hz, 1H), 4.55–4.75 (m, 3H), 4.87 (d, J = 2.3 Hz, 1H),
5.89 (d, J = 3.91 Hz, 1H), 6.94–7.01 (m, 1H), 7.17–7.25 (m, 2H), 7.35–
7.41 (m, 1H). 13C NMR (50 MHz, CDCl3) d: 26.3 (q), 26.9 (q), 67.4
(t), 73.5 (d), 80.1 (d), 84.7 (d), 105.2 (d), 111.6 (s), 124.2 (d), 127.4 (d),