Baylis-Hillman reaction based flexible strategy for the synthesis of gabosine I, gabosine G, epi-gabosine i and carba l-pentose

Article abstract of DOI:10.1016/j.tetlet.2011.11.134

A combination of diastereoselective Baylis-Hillman reaction and RCM reaction set is used as the flexible strategy for the ready access to cyclohexenoid and cyclopentenoid skeletons.

Full text of DOI:10.1016/j.tetlet.2011.11.134

Tetrahedron Letters 53 (2012) 744–747
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Tetrahedron Letters
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Baylis–Hillman reaction based flexible strategy for the synthesis of gabosine I,
gabosine G, epi-gabosine I and carba L-pentose
⇑
Palakodety Radha Krishna , Raghu Ram Kadiyala
D-211, Discovery Laboratory, Organic & Biomolecular Chemistry Division, CSIR, Indian Institute of Chemical Technology, 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:
A combination of diastereoselective Baylis–Hillman reaction and RCM reaction set is used as the flexible
strategy for the ready access to cyclohexenoid and cyclopentenoid skeletons.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 14 September 2011
Revised 25 November 2011
Accepted 27 November 2011
Available online 6 December 2011
Keywords:
Cyclitols
Cyclohexitols
Cyclopentitol
Baylis–Hillman reaction
Ring-closing metathesis (RCM)
Carba-L-furanose
Gabosines belong to a family of unusual, C7 skeleton containing
hydroxylated cyclohexenones that may be classified as pseudo or
carbasugars since they show structural similarities to carbohydrates
and are considered being derived from secondary metabolism
(Fig. 1). They were isolated from Streptomyces strains1 and display
interesting biological activities such as antibiotic, anticancer, and
DNA binding properties. So far three syntheses have been reported
for gabosine I 1. The first total synthesis of gabosine I was achieved
chemically diverse hydroxyl groups eventually leading to the cor-
responding polyols. In order to expand the synthetic horizon of
BH-adducts and find newer uses of olefinic functionality, we
embarked on a program of using the hydroxyl group either as its
acrylate derivative in the metathesis reaction6e or involving the
olefin directly in the metathesis reaction resulting in diverse prod-
ucts in each case.6f Taking this inspiration further, herein we report
the total synthesis of gabosine I 1, epi-gabosine I 2, gabosine G 3,
by Lubineau and Billault2 from tetra-O-benzyl-
D
-glucose using
and carba-L-furanose 4 wherein the highly functionalized
intramolecular Nozaki–Hiyama–Kishi reaction. The second synthe-
sis of gabosine I 1 and gabosine G 3 was achieved by Shing3 using
one-pot TPAP oxidation–K2CO3-mediated intramolecular Horner–
Wadsworth–Emmons (HWE) olefination as the key step. More
recently, Shing4 described yet another synthesis of gabosine I.
RCM has been extensively used for the synthesis of carbasu-
gars.5a–d Interestingly, non-RCM based approaches are equally
important synthetic strategies for such targets.5e–h Herein an alter-
nate way of accessing the requisite RCM precursor via diastereose-
lective Baylis–Hillman reaction is conceived. Incidentally,
Baylis–Hillman reaction offers a multifunctional adducts as prod-
ucts constituting a b-hydroxy acrylate moiety.6a–c These BH-ad-
ducts, endowed with an olefinic moiety, were earlier transformed
by us6d into higher-carbon sugars wherein the olefin was assumed
to be a masked ketone that was generated through ozonolysis of
the adduct. The ketone on subsequent reduction afforded stereo-
Baylis–Hillman adduct 7 was identified as a common intermediate
suitable for accessing all the products. Thus the diastereomeric
mixture of adduct 7 was conceived as a common substrate for
accessing three cyclitols (1, 3 and an epimer 2) besides an impor-
tant cyclopentitol derivative 4 using the metathesis reaction as
the second key reaction.
The diastereoselective Baylis–Hillman reaction of chiral alde-
hyde derived from threitol 5, with ethyl acrylate in DMSO as the
solvent and DABCO as the base resulted in 7 (85%) as a chromato-
graphically inseparable isomeric mixture. We7a,b and other
researchers7c,d have shown that polar solvents like DMSO, DMF
etc., not only help in stabilizing the Zwitterionic intermediate but
also enhance the pKa of the reaction medium and help in faster
reaction rates. Of all the bases8 tested, DABCO was found to be bet-
ter suited when used in combination with DMSO as solvent. These
reaction conditions are suitable for less reactive aldehydes. For a
chiral aldehyde the stereochemical outcome could be predicted
invoking a Felkin–Ahn model9 and normally an anti product is
the major isomer. Since the aldehyde precursor possesses an
⇑
Corresponding author. Tel.: +91 4027193158; fax: +91 4027160387.
E-mail address: prkgenius@iict.res.in (P. Radha Krishna).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.134

P. Radha Krishna, R. R. Kadiyala / Tetrahedron Letters 53 (2012) 744–747
745
OH
OAC
OH
3
OBn
OH
3
3
OH
OH
BnO
BnO
2
2
2
4
4
4
5
5
5
6
6
6
O
OH
1
O
OH
O
OH
1
1
OBn
OH
OH
gabosine G 3
OH
epi-gabosine I 2
carba L-pentose 4
gabosine I 1
Figure 1. Various cyclitols synthesized.
O
HO
O
O
O
O
TBDPSO
OH
OH
a
OH
b, c
OTBDPS
O
O
O
O
7
6
2, 3-O-isopropylidine-
L-threitol 5
OH
O
OH
TBDPSO
d
f
e
TBDPSO
O
O
O
O
8
9
O
O
O
O
+
HO
HO
O
O
O
O
10a
10
Scheme 1. Reagents and conditions: (a) TBDPS-Cl, imidazole, CH2Cl2, 12 h, 79%; (b) (COCl)2, dry DMSO, dry CH2Cl2, Et3N, ꢀ78 °C; (c) Ethyl acrylate, DABCO, DMSO, 24 h, 30%
de; (d) DIBAL-H,CH2Cl2, ꢀ20 °C, 3 h, 91%; (e) 2,2-DMP, PTSA, CH2Cl2, 0 °C, 12 h, 94%; (f) TBAF, THF, 5 h.
O
OH
O
O
O
O
O
O
O
c
a, b
HO
O
O
O
HO
O
10a
12
11
O
OH
O
O
d
e
OH
O
O
OH
O
13
OH
Gabosine I 1
Scheme 2. Reagents and conditions: (a) (COCl)2, dry DMSO, dry CH2Cl2, Et3N, ꢀ78 °C; (b) vinylMgBr, THF, ꢀ20 °C, 0.33 h, 87%; (c) G-II catalyst, toluene, reflux, 5 h, 83%; (d)
DMP, CH2Cl2, 0 °C, 2 h, 96%; (e) TFA, CH2Cl2, 0 °C, 2 h.
adjacent stereogenic carbon, the newly created center bears an
anti-relationship (major isomer) to the existing one. Thus the new-
ly created stereogenic center of the major isomer in 7 was assigned
as ‘S’ and the minor isomer as ‘R’ based on our previous
observation.10 The major isomer on further transformations affor-
ded bis-olefin which on ring-closing metathesis (RCM) followed
by oxidation and deprotection gave epi-gabosine I 2. The same
set of reactions when applied for minor isomer gave gabosine I 1
(Scheme 2). The chirality could be enriched or reversed by adopt-
ing the ‘double asymmetric induction’ protocol.10 However, herein
we proceeded with the isomeric mixture (7) since two targets
could be obtained.
OH
OH
OAc
OH
ref. 3
O
OH
OH
gabosine I 1
O
OH
OH
gabosine G 3
Scheme 3. Gabosine I can be converted to gabosine G using known procedure.
silylated 2,3-O-isopropylidine-L-threitol 6 (79%, Scheme 1). Pri-
mary alcohol 6 on oxidation under Swern conditions furnished
the corresponding aldehyde (96%), Baylis–Hillman reaction of
Accordingly, selective TBDPS protection of 2,3-O-isopropyli-
dine-L-threitol 5 (TBDPS-Cl/imidazole/CH2Cl2) gave the mono

746
P. Radha Krishna, R. R. Kadiyala / Tetrahedron Letters 53 (2012) 744–747
O
O
O
OH
O
O
O
O
O
c
a, b
O
HO
O
O
HO
O
O
10
14
15
OH
O
O
d
e
OH
O
O
OH
O
OH
epi-gabosine I 2
16
Scheme 4. Reagents and conditions: (a) (COCl)2, dry DMSO, dry CH2Cl2, Et3N, ꢀ78 °C; (b) vinylMgBr, THF, ꢀ20 °C, 0.2 h, 87%; (c) G-II catalyst, toluene, reflux, 5 h, 83%; (d)
DMP, CH2Cl2, 0 °C, 2 h, 96%; (e) TFA, CH2Cl2, 0 °C, 2 h.
O
O
O
O
OBn OBn
OBn
BnO
BnO
a, b
e
c, d
HO
O
O
O
OBn
O
BnO
OBn
10
18
4
17
Scheme 5. Reagents and conditions: (a) (COCl)2, dry DMSO, dry CH2Cl2, Et3N, ꢀ78 °C; (b) CHþ PPh3Iꢀ, KOtBu, THF, 0 °C, 8 h; (c) TFA, CH2Cl2, 0 °C, 2 h; (d) NaH, Bn–Br, THF,
3
12 h, 0 °C; (e) HG-II catalyst, toluene, reflux, 5 h, 86%.
aldehyde and ethyl acrylate in the presence of DABCO in DMSO at
room temperature gave BH-adduct 7 (85%, 30% de) as an insepara-
ble mixture of compounds. The de was evaluated using 1H NMR
wherein the differential integral values of olefinic protons appear-
ing at d 6.30 ppm (s, 0.35H) and at d 6.27 ppm (s, 0.65H) gave the
ratio of isomers, while the absolute stereochemistry of major iso-
mer was assigned as ‘S’ based on our previous observation.10 Next,
reduction of the ester group in 7 {DIBAL-H/CH2Cl2/ꢀ20 °C/3 h} fur-
nished the allyl alcohol 8 (91%). The ensuing 1,3 diol moiety in 8
was protected as its acetonide (2,2-DMP/PTSA/CH2Cl2) to afford 9
(94%). TBDPS deprotection of 9 with TBAF afforded two separable
isomers 10 and 10a (57.8% and 31.2% respectively, overall 89%).
The two isomers on further transformations independently, gave
gabosine I and epi-gabosine I.
Initially, the minor isomer 10a was taken up for the rest of the
synthetic sequence (Scheme 2). Accordingly, the primary alcohol of
10a on oxidation under Swern conditions followed by vinylation
{vinylMgBr/THF/ꢀ20 °C/0.33 h} afforded the allyl alcohol 11 (87%,
Scheme 2) as a 1:1 mixture. No effort was made to separate the iso-
mers since the carbon bearing the newly created hydroxyl group
later manifests into a ketone functionality. The bis-olefin on ring-
closing metathesis11 (Grubbs II catalyst/toluene/110 °C) afforded
substituted cyclohexene derivative 12 (83%). Subsequently, 12 on
oxidation12 {DMP/CH2Cl2/0 °C} furnished diacetonide 13 (89%). Fi-
nally acetonide deprotection {TFA in CH2Cl2/0 °C} gave gabosine I 1
(95%). Compound 1 was characterized from its spectral data. Thus,
1H NMR spectrum revealed the lone olefinic proton appeared at d
6.15 ppm as a doublet (J = 1.8 Hz), the allylic proton appeared at
d 4.95 ppm as a doublet (J = 4.5 Hz) and the characteristic methine
next to ketone functionality resonated at d 4.33 as a doublet
(J = 13.5 Hz). Thus the physical and spectroscopic data of synthetic
1 are consistent with the reported values.2,3 Literature inspired3
conversion of 1 gave 3 (Scheme 3).
Grubbs catalyst assisted11 ring-closing metathesis (Grubbs II
catalyst/toluene/110 °C) afforded cyclohexene ring 15 (83%).
Compound 15 on oxidation (DMP/CH2Cl2/0 °C) gave the diaceto-
nide derivative 16 (96%). Finally, acetonide deprotection (TFA in
CH2Cl2/0 °C) furnished epi-gabosine I 2 (95%). Compound 2 was
thoroughly characterized from its spectral data. HRMS spectrum
of
2
displayed the [M+Na]+ at 197.0435, calculated gave
197.0425 for the molecular formula C7H10O5Na as an additional
support.
Alternative use of 10 was envisioned (Scheme 5). Accordingly,
primary alcohol 10 on Swern oxidation followed by Wittig olefin-
ation (CH3+PPh3Iꢀ/KOtBu/THF/0 °C/8 h) afforded the bis-olefin 17
(81%), deprotection of acetonide group (TFA/CH2Cl2/0 °C) gave te-
trol that was protected as its benzyl ether (BnBr/NaH/THF/0 °C)
to furnish the tetra benzyl protected bis-olefin 18 (73% over two
steps). Hoveyda–Grubbs catalyzed ring-closing metathesis13 (HG-
II/toluene/reflux/5 h) of bis-olefin 18 afforded the carba-L-sugar 4
(86%). Interestingly 4 constitute an important synthetic precursor
to access carbanucleosides and the strategy disclosed herein offers
its practical approach.14 Thus a rare and non-natural carba-
was synthesized herein.
L-sugar
In conclusion, we demonstrated the synthesis of gabosine I, epi-
gabosine I and gabosine G from the common intermediate derived
from diastereoselective Baylis–Hillman reaction.15 Alongside, the
synthesis of cyclopentenoid derivative, accessed through this pro-
tocol demonstrated the versatility and generality of the strategy.15
The protocol described herein is general and amenable for the syn-
thesis of similar cylcitols.
Acknowledgment
One of authors (R.R.K.) thanks CSIR, New Delhi, for financial
support in the form of a fellowship.
Similarly, the major adduct 10 on oxidation under Swern condi-
tions followed by vinylation (vinylMgBr/THF/ꢀ20 °C/20 min) affor-
ded the allyl alcohol 14 (87%) as a 1:1 isomeric mixture (Scheme 4).
Here too no efforts were made to separate the isomers because of
its transformation into a ketone functionality. The bis-olefin on
References and notes
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P. Radha Krishna, R. R. Kadiyala / Tetrahedron Letters 53 (2012) 744–747
747
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109.4, 80.3, 77.8, 72.5, 66.3, 63.4, 29.4, 27.4; ESIMS: 281 (M+Na)+, HRMS m/z:
Calcd for
C13H22O5Na: 281.1364, Found: 281.1368. Compound 10a: Pale
5. (a) Callam, C. S.; Lowory, T. L. Org. Lett. 2000, 2, 167–169; (b) Callam, C. S.;
Lowory, T. L. J. Org. Chem. 2001, 66, 8961–8972; (c) Banerjee, S.; Nayyek, A.;
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3848–3851; (e) Carpintero, M.; Mayoralas, A. F.; Jaramillo, C. J. Org. Chem. 1997,
62, 1916–1917; (f) Mehta, G.; Mohal, N. Tetrahedron Lett. 1998, 39, 3285–3286;
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B. Tetrahedron Lett. 2007, 48, 6466–6470; (e) Radha Krishna, P.; Narasingam,
M.; Kannan, V. Tetrahedron Lett. 2004, 45, 4773–4775; (f) Radha Krishna, P.;
Narasingam, M. J. Comb. Chem. 2007, 9, 62–69.
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Lett. 2004, 45, 1183–1185; (b) Radha Krsihna, P.; Manjuvani, A.; Raja Sekhar, E.
ARKIVOC 2005, iii, 99–109; (c) Yu, C. Z.; Liu, B.; Hu, L. Q. J. Org. Chem. 2001, 66,
5413–5418; (d) Price, K. E.; Broadwater, S. J.; Jung, H. M.; McQuade, D. T. Org.
Lett. 2005, 7, 147–150.
8. (a) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc.
1999, 121, 10219–10220; (b) Aggarwal, V. K.; Dean, D. K.; Mereu, A.; Williams,
R. J. Org. Chem. 2002, 67, 510–514; (c) Faltin, C.; Fleming, E. M.; Connon, S. J. J.
Org. Chem. 2004, 69, 6496–6599; (d) Radha Krishna, P.; Raja Sekhar, E.; Kannan,
V. Synthesis 2004, 857–860; (e) Radha Krishna, P.; Kannan, V.; Narasimha
Reddy, P. V. Adv. Synth. Cat. 2004, 346, 603–606.
yellow syrup. ½a D25
ꢁ
ꢀ66.9 (c 0.5, CHCl3). 1H NMR (300 MHz, CDCl3): d; 5.13 (s,
1H), 5.02 (s, 1H), 4.50 (br s, 1H), 4.33 (d, 1H, J = 12.1 Hz) 4.23–4.14 (m, 3H), 3.81
(d, 1H, J = 11.5 Hz), 3.67 (m, 1H), 1.43–1.35 (m, 12H). 13C NMR (75 MHz,
CDCl3): d 142.2, 109.5, 109.1, 99.9, 77.8, 76.5, 69.1, 64.4, 62.4, 27.1, 26.6;
ESIMS: 281 (M+Na)+, HRMS m/z: Calcd for C13H22O5Na: 281.1365, Found:
281.1367. Compound 13: Colorless syrup ½a D25
ꢁ
ꢀ33.1 (c 0.44, CHCl3). 1H NMR
(300 MHz, CDCl3): d 5.83 (s, 1H), 4.80 (d, 1H, J = 8.0 Hz), 4.60–4.44 (2d, 2H),
4.16 (d, 1H, J = 10.6 Hz), 3.99 (dd, 1H, J = 10.2, 8.4 Hz), 1.59 (s, 3H), 1.51 (s, 6H),
1.46 (s, 3H). 13C NMR (75 MHz, CDCl3): d 195.2, 156.7, 121.5, 112.3, 102.9, 76.4,
74.7, 65.3, 64.6, 28.5, 26.4, 22.8 cmꢀ1. ESIMS: m/z 277 (M+Na)+. Anal. Calcd for
C
13H18O5 (254.115): C, 61.40; H, 7.14. Found: C, 61.22, H, 6.98. Compound 1:
Solid mp 99–101 °C. ½a D25
ꢁ
ꢀ57.5 (c 0.3, MeOH). 1H NMR (300 MHz, CD3OD): d
6.15 (d, 1H, J = 1.8 Hz), 4.51 (d, 1H, J = 18.5 Hz, H-4), 4.39–4.29 (m, 2H, H-5),
4.03 (d, 1H, J = 10.5 Hz, H-6), 3.58 (dd, 1H, J = 10.5, 8.6 Hz, H-5). 13C NMR
(75 MHz, CDCl3): d 199.5, 168.1, 121.3, 79.5, 78.1, 73.7, 62.1. IR (neat): 3435,
1742, 1621 cmꢀ1
. HRMS m/z: Calcd for: C7H10O5Na: 197.0425. Found:
197.0429. Compound 16: Colorless syrup. ½a D25
ꢁ
+33.1 (c 0.44, CHCl3). 1H
NMR (300 MHz, CDCl3): d 5.86 (d, 1H, J = 1.5 Hz), 4.95 (d, 1H, J = 4.5 Hz), 4.70–
4.62 (m, 2H), 4.33 (d, 1H, J = 13.5 Hz), 3.95 (dd, 1H, J = 10.5, 5.2 Hz), 1.64 (s, 3H),
1.51 (d, 6H, J = 3.0 Hz), 1.46 (s, 3H). 13C NMR (75 MHz, CDCl3): d 193.7, 152.7,
121.6, 112.7, 101.9, 74.7, 65.3, 64.6, 60.4, 29.6, 27.7, 26.4, 21.7. IR (neat): 1735,
1620 cmꢀ1. ESIMS: m/z 277 (M+Na)+. Anal. Calcd for C13H18O5 (254.115): C,
61.40; H, 7.14. Found: C, 60.87, H, 7.33. Compound 2: Solid mp 118–119 °C.
½ ꢁ
a 2D5 +76.5 (c 0.5, MeOH); 1H NMR (300 MHz, CD3OD): d 6.12 (s, 1H), 4.41 (d,
1H, J = 18 Hz, H-4), 4.34 (d, 1H, J = 10.2 Hz, H-6), 4.27–4.23 (m, 2H, H-5), 3.70
(dd, 1H, J = 10.2, 3.8 Hz, H-5). 13C NMR (75 MHz, CDCl3): d 200.1, 164.2, 122.9,
74.8, 74.2, 68.2, 63.3. IR(neat): 3435, 1742, 1621 cmꢀ1. HRMS m/z: Calcd for:
9. Roush, W. R.; Adam, M.; Walts, A. E.; Harris, D. J. Am. Chem. Soc. 1986, 108,
3422–3434.
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12. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
C7H10O5Na: 197.0425. Found: 197.0435. Compound 17: Colorless syrup. ½a D25
ꢁ
+31.9 (c 0.8, CHCl3). 1H NMR (300 MHz, CDCl3): d 5.81–5.95 (m, 1H), 5.28–5.39
(m, 1H), 5.12 (br s, 2H), 4.92 (s, 1H), 4.46–4.32 (m, 1H), 4.22 (br s, 1H), 4.13–
4.03 (m, 1H), 3.92–3.90 (s, 1H), 3.61–3.55 (m, 1H), 1.48–1.32 (m, 12H). 13C
NMR (75 MHz, CDCl3): d 143.0, 136.6, 135.6, 118.8, 109.4, 108.17, 80.5, 77.8,
68.9, 64.25, 27.1, 26.3. ESIMS: m/z 277 (M+Na)+. Anal. Calcd for C14H22O4
(254.150): C, 66.12; H, 8.72. Found: C, 65.96, H, 8.34. Compound 4: Colorless
13. Radha Krishna, P.; Kadiyala, R. R. Tetrahedron Lett. 2010, 51, 4981–4983.
14. (a) Gillaizeau, I.; Charamon, S.; Agrofogli, L. A. Tetrahedron Lett. 2001, 42, 8817–
8819; (b) Yoshida, N.; Kamikubo, T.; Ogasawara, K. Tetrahedron Lett. 1998, 39,
4677–4678; (c) Ono, M.; Nishimura, K.; Tsubouchi, H.; Nagaoka, Y.; Tomioka, K.
J. Org. Chem. 2001, 66, 8199–8203.
syrup. ½a 2D5
ꢁ
+80.5 (c 0.65, CHCl3). 1H NMR (300 MHz, CDCl3): d 7.35–7.11 (m,
20H), 5.99 (s, 1H), 4.83–4.76 (m, 1H), 4.72–4.55 (m, 7H), 4.49 (d, 2H,
J = 12.0 Hz), 4.15–4.05 (m, 2H), 4.02 (t, 1H, J = 5.0 Hz). 13C NMR (75 MHz,
CDCl3): d 142.3, 138.5, 138.4, 138.3, 138.1, 130.3, 128.5, 128.4, 128.3, 128.0,
128.1, 127.8, 127.7, 127.7, 127.6, 86.4, 84.4, 72.7, 72.3, 71.9, 71.5, 67.2. ESIMS:
m/z 529 (M+Na)+. Anal. Calcd for C13H34O4 (506.245): C, 80.60; H, 6.76. Found:
C, 80.42, H. 6.23.
15. Spectral data for selected compounds: Compound 10: Pale yellow syrup. ½a D25
ꢁ
+34.6 (c 0.8, CHCl3). 1H NMR (300 MHz, CDCl3): d 5.23 (s, 1H), 5.02 (s, 1H),
4.35–4.32 (m, 2H), 4.23 (d, 1H, J = 13.3 Hz), 4.12–4.07 (m, 1H), 3.94–4.00 (m,
1H), 3.82–3.78 (dd, 1H, J = 11.4, 4.4 Hz), 3.75–3.66 (m, 1H), 1.42 (d, 6H,
J = 4.4 Hz), 1.37 (d, 6H, J = 9.9 Hz). 13C NMR (75 MHz, CDCl3): d 141.1, 110.0,