'Off template site' [3+3] annulation reaction on sugar derived enal: Stereoselective synthesis of C-C-linked pseudo-saccharide precursors

Article abstract of DOI:10.1016/S0957-4166(00)00222-6

A [3+3] annulation protocol at an 'off template' site of a sugar-derived enal synthon is used effectively for the stereoselective synthesis of C-C-linked pseudo-saccharide precursors. The chirality is induced from the sugar synthon during the installation of carbocycle at the C-5 of sugar template. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00222-6

Tetrahedron: Asymmetry 11 (2000) 2643±2646
`O€ template site' [3+3] annulation reaction on sugar derived
enal: stereoselective synthesis of C±C-linked
pseudo-saccharide precursorsy
G. V. M. Sharma,a,* A. Subhash Chander,a Palakodety Radha Krishna,a
K. Krishnudu,a M. H. V. Ramana Raob and A. C. Kunwarb
aDiscovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
bNMR Group, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 19 January 2000; accepted 18 May 2000
Abstract
A [3+3] annulation protocol at an `o€ template' site of a sugar-derived enal synthon is used e€ectively for
the stereoselective synthesis of C±C-linked pseudo-saccharide precursors. The chirality is induced from the
sugar synthon during the installation of carbocycle at the C-5 of sugar template. # 2000 Elsevier Science
Ltd. All rights reserved.
The development of novel and ecient methods for the stereoselective construction of carbo-
cycles1 is an area of signi®cant current activity. A variety of useful approaches for this purpose
are found in the literature, such as intramolecular Diels±Alder reaction, double Michael cyclisation,
1,3±dipolar cycloadditions and radical induced reactions.2 As part of our ongoing e€orts on the
transformation of sugars into C-glycosides,3,4 C±C linked disaccharides,5 C-linked spiro saccharides6
etc. herein, we describe the synthesis of C±C linked pseudo-saccharide precursors7 1, 2 and 3,
adopting a Michael±Wittig reaction on a sugar-derived enal.
* Corresponding author. E-mail: esmvee@iict.ap.nic.in
y
IICT communication no. 4167.
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00222-6

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Accordingly, known aldehyde 4,8 prepared from diacetone glucose, on Wittig ole®nation
(Scheme 1), was converted into a,b-unsaturated ester 5 (82%), which, on DIBAL-H reduction,
followed by oxidation of alcohol 6 with PDC, resulted in enal 7 (95%). H NMR spectrum of 7
1
has the H-5 at ꢀ 6.74 (dd, J4,5=5.8, J5,6=14.7 Hz), and H-6 at ꢀ 6.32 (dd, J5,6=14.7, J6,7=8.8
Hz) indicating trans disposition of the ole®nic double bond. The crucial [3+3] annulation reaction
on the ole®n 7 with ethyl 3-oxo-4-(triphenylphosphorylidene)butanoate A,9 in the presence of
NaH and a drop of water10 in THF at 50ꢀC for 10 min, resulted in the formation of 8a, 8b and 8c
as a mixture of diastereoisomers (6:1.5:2.5, HPLC-ODS preparative column, MeOH:H2O, 7:3,
UV 225 nm) in a combined yield of 75%. The stereochemical outcome of annulation products 8a
1
and 8b was unambiguously determined by H NMR spectrum. The formation of 8a as a major
product is in accordance with the literature,11 evidence for the Michael addition of the sodium
enolate of A on the g-alkoxy enal system 7.
Scheme 1. (a) Ph3PˆCHCO2Et, C6H6, re¯ux, 82%; (b) DIBAL-H, CH2Cl2, ^20ꢀC, 86%; (c) PDC, CH2Cl2, re¯ux,
95%; (d) Ph3PˆCHCOCH2CO2Et (A), NaH, two drops water, THF, 50ꢀC, 75%
The mixture of major compounds 8a and 8b, separated from 8c by column chromatography
(Si-gel, 200 mesh, EtOAc:Pet. ether, 1:4) was subjected to NaBH4 (Scheme 2) reduction under
Luche's12 reaction conditions to a€ord alcohols 9 (major), 10 (minor) and 11 (one isomer) in the
ratio of 4:1:2 respectively in a combined yield of 88% from 8a+8b. Acetylation of alcohols 9, 10
ꢀ
.
Scheme 2. (a) NaBH4, CeCl3 7H2O, EtOH, 0 C, 88%; (b) Ac2O±Py; (c) OsO4±NMO, CH3COCH3:H2O (3:1)

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 11 (2000) 2643±2646
2645
and 11 with Ac2O-pyridine gave the acetates 12, 13 and 14, respectively, whose structures were
assigned from the spectral data. anti-Facial stereoselective cis-dihydroxylation13 of the ole®ns 12,
13 and 14 was e€ected using OsO4±NMO in acetone:water (3:1) system to a€ord the diols 15, 16
and 17, respectively, which, on subsequent acetylation, gave the corresponding acetates 1, 2 and
3, respectively. All the C±C-linked pseudo-saccharide precursors are thoroughly characterized
1
from the H NMR (vicinal couplings (J) as well as the data from the NOESY experiments) and
other spectral data.14
Compound 1 has shown characteristic NOE cross-peaks H6±H8, H6±H10ax, H8±H10ax and
H5±H7 and J5,6, J6,7, J7,8 and J5,10ax values of about 10.0 Hz consistent with a chair conformation
8
(Fig. 1; C5), most of the substituents in equatorial position. The structure of 2 is supported by
strong NOE cross-peaks between H5±H9 and H6±H10ax as well as a large value of about 10.0 Hz
for J5,6, J5,10ax and J9,10eq, while large NOE cross-peaks between H5±H7 as well as J5,10ax=13.0
Hz and J7,8=10.8 Hz con®rm the structure of 3. Thus, in all the three pseudo-saccharide pre-
8
cursors 1, 2 and 3 the carbocycle ring has C5 chair conformation. Small values of J1,2, J2,3 and
J3,4 point to a twist conformation for the sugar ring. The presence of NOE cross-peaks between
H1-Me(A) and H2-Me(A) implies an envelope conformation for the ®ve-membered ring con-
taining the isopropylidine group. The relative orientation of the carbocycle and sugar ring is
con®rmed by the strong NOE cross-peaks between H3±H10eq, H4±H10ax and weak NOE cross-
peaks between H3±H10ax, H4±H10eq and H10eq±OMe. The NMR data compare well with the
energy minimized structures obtained from PCMODEL.15
We have demonstrated the installation of the carbocycle ring system at C-5 of the sugar synthon,
by adopting an `o€ template site' stereoselective [3+3] annulation approach, where the chirality of
the carbocycle is induced from the sugar template. Due to the ready availability of reagents and
simple reaction conditions, the present protocol should ®nd application for the synthesis of several
pseudo-saccharide precursors.
Figure 1.

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G. V. M. Sharma et al. / Tetrahedron: Asymmetry 11 (2000) 2643±2646
Acknowledgements
One of the authors, A. Subhash Chander, is thankful to UGC, New Delhi, for ®nancial support.
This work was supported by a Grant-in-Aid project (CSIR Young Scientist Award to Dr. G. V. M.
Sharma).
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5. Sharma, G. V. M.; Hymavathi, L.; Radha Krishna, P. Tetrahedron Lett. 1997, 38, 6929±6932.
6. Sharma, G.V.M.; Goverdhan Reddy, V.; Radha Krishna, P. Tetrahedron Lett. 1999, 40, 1783±1786.
7. Jacques, F.; Dupeyroux, H.; Joly, J.-P.; Chapleur, Y. Tetrahedron Lett. 1997, 38, 73±76.
8. Tronchet, J. M. J.; Baehler, B. J.; Eder, H.; Le Hong, F.; Perret, N.; Poncet, J.; Zumbwald, B. J. Helv. Chem. Acta.
1973, 56, 1310±1313.
9. Chem. Abstr. 1967, 66, 2623f.
10. Pietrusiewicz, K. M.; Monkiewicz, J. J. Org. Chem. 1983, 48, 788±790.
11. Leonard, J.; Mohialdin, S.; Redd, D.; Ryan, G.; Jones, M. F. J. Chem. Soc., Chem. Commun. 1993, 23±25.
12. Luche, J. L.; Rodriqorg-Hannh, Crabbe, P. J. Chem. Soc., Chem. Commun. 1978, 601±602.
13. Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40, 2247±2255.
14. Selected spectral data: compound 1: m.p. 95±97ꢀC; [ꢁ]D=^53.4 (c 1.7, CHCl3). H NMR (400 MHz, CDCl3) ꢀ:
1
1.25 (t, 3H, J=7.1 Hz, ^OCH2CH3), 1.28 (s, 3H, Me(A)), 1.45 (s, 3 H), 1.52 (ddd, 1H, J5,10a=12.4, J10a,10e=13.6,
J9,10a=2.3 Hz, H-10a), 1.98 (s, 3H, ^OAc), 1.99 (s, 3H, ^OAc), 2.02 (dt, 1H, H-10e), 2.13 (s, 3H, ^OAc), 2.56 (dd,
1H, J5,6=11.3, J6,7=10.5 Hz, H-6), 2.65 (m, 1H, J5,10e=3.5 Hz, H-5), 3.35 (s, 3H, OMe), 3.60 (d, 1H, J3,4=2.9
Hz, H-3), 3.93 (dd, 1H, J3,4=2.9, J4,5=8.8 Hz, H-4), 4.13 (q, 2H, J=7.1 Hz, ^OCH2CH3), 4.51 (d, 1H, J1,2=3.9 Hz,
H-2), 4.88 (dd, 1H, J7,8-9.9, J8,9=3.1 Hz, H-8), 5.33 (m, 1H, J9,10a=2.3, J9,10e=4.2 Hz, H-9), 5.60 (t, 1H, H-7),
5.80 (d, 1H, J1,2=3.9 Hz, H-1); 13C NMR (50 MHz, CDCl3) ꢀ: 13.31, 20.64, 20.98, 26.17, 26.83, 28.02, 29.53,
33.16, 47.08, 57.20, 60.38, 68.62, 70.37, 72.32, 80.85, 81.06, 85.32, 104.56, 111.38, 168.11, 170.18, 170.24, 170.88;
MS (FAB) m/z (%): 503 (36), 487 (11), 457 (100), 443 (27); HR-MS (FAB): calcd for (M^OEt) C21H29O11:
1
457.170987; found: 457.169200; compound 2: [ꢁ]D=+3.2 (c 0.5, CHCl3); H NMR (400 MHz, CDCl3) ꢀ: 1.24 (t,
3H, J=7.1 Hz, ^OCH2CH3), 1.31 (s, 3H, CH3(A)), 1.49 (s, 3H, CH3(B)), 1.64 (dt, 1H, J5,10a=9.8, J9,10a=9.9,
J10a,10e=13.2 Hz, H-10a), 1.99 (dt, 1H, J10a,10e=13.2, J9,10e=4.2, J5,10e=4.8 Hz, H-10e), 2.03, 2.08, 2.10 (3s, 9H,
^OAc), 2.67 (dq, 1H, J5,10e=4.8 Hz, H-5), 2.92 (dd, 1H, J5,6=9.1, J6,7=3.5 Hz, H-6), 3.40 (s, 3H, ^OMe), 3.57 (d,
1H, J3,4=3.0 Hz, H-3), 4.10 (qd, 2H, J=7.1 Hz, ^OCH2CH3), 4.11 (dd, 1H, J3,4=3.0, J4,5=9.1 Hz, H-4), 4.55 (d,
1H, J1,2=3.8 Hz, H-2), 5.30 (ddd, 1H, J8,9=3.2, J9,10a=9.9, J9,10e=4.2 Hz, H-9), 5.34 (dd, 1H, J7,8=6.0, J8,9=3.2
Hz, H-8), 5.42 (dd, 1H, J6,7=3.5, J7,8=6.0 Hz, H-7), 5.83 (d, 1H, J1,2=3.8 Hz, H-1); 13C NMR (50 MHz, CDCl3)
ꢀ: 13.85, 20.77, 20.83, 26.21, 26.27, 26.74, 28.62, 32.85, 44.71, 57.32, 60.81, 67.70, 68.21, 68.59, 80.66, 81.30, 83.73,
104.50, 111.54, 160.33 (2C), 160.80, 171.18; MS (FAB) m/z (%): 503 (100), 457 (52), 443 (22); HR-MS (FAB):
calculated for (M+1) C23H35O12: 503.212852; found: 503.210874; compound 3: m.p. 95±97ꢀC; [ꢁ]D=^54.5 (c 2.3,
1
CHCl3), H NMR (400 MHz, CDCl3) ꢀ: 1.28 (t, 3H, J=7.1 Hz, ^OCH2CH3), 1.31 (s, 3H, CH3(A)), 1.41 (s, 3H,
CH3(B)), 1.64 (dt, 1H, J9,10e=5.8, J5,10e=3.3, J10a,10e=14.2 Hz, H-10e), 2.00, 2.01, 2.09 (3s, 9H, ^OAc), 2.23 (m,
1H, J9,10e=2.5, J5,10a=13.0 Hz, H-10a), 2.58 (m, 1H, J4,5=10.5, J5,6=4.2, J5,10e=3.3 Hz, H-5), 3.36 (s, 3H,
^OMe), 3.53 (t, 1H, H-6) 3.54 (d, 1H, J3,4=3.0 Hz, H-3), 3.83 (dd, 1H, J3,4=2.9, J4,5=10.5 Hz, H-4), 4.11±4.25
(m, 2H, ^OCH2CH3), 4.54 (d, 1H, J1,2=3.8 Hz, H-2), 5.36 (dd, 1H, J7,8=10.8 Hz, H-7), 5.44 (m, 1H, J8,9=3.3 Hz,
H-9), 5.6 (dd, 1H, J8,9=3.3, J7,8=10.8 Hz, H-8), 5.85 (d, 1H, J1,2=3.8 Hz, H-1); 13C NMR (50 MHz, CDCl3) ꢀ:
14.31, 20.69, 20.76, 26.25, 26.40, 26.61, 29.64, 31.30, 45.15, 57.66, 60.60, 69.16, 69.57, 69.68, 79.93, 80.97, 83.23,
104.60, 111.48, 169.75, 169.97, 170.19, 171.30; MS (FAB) m/z (%): 503 (36), 457 (52), 279 (100); HR-MS (FAB):
calculated for (M+1) C23H35O12: 503.212852; found: 503.214328.
15. PCMODEL, Gilbert, K. E.; Gajewski, J. J. Senna Software, Box 3076, Bloomington IN47402, USA.