Total synthesis of (+)-pericosine B and (+)-pericosine C and their enantiomers by using the Baylis-Hillman reaction and ring-closing metathesis as key steps

Article abstract of DOI:10.1016/j.tetlet.2011.10.135

A simple and divergent route for the total synthesis of pericosine B and pericosine C and their enantiomers from d-ribose by using the Baylis-Hillman reaction and ring-closing metathesis reactions as key steps has been described.

Full text of DOI:10.1016/j.tetlet.2011.10.135

Tetrahedron Letters 53 (2012) 132–136
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of (+)-pericosine B and (+)-pericosine C and their enantiomers
by using the Baylis–Hillman reaction and ring-closing metathesis as key steps
⇑
Y. Suman Reddy, P. Kadigachalam, Ranjan K. Basak, A.P. John Pal, Yashwant D. Vankar
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and divergent route for the total synthesis of pericosine B and pericosine C and their enantio-
Received 30 September 2011
Revised 19 October 2011
Accepted 22 October 2011
Available online 4 November 2011
mers from
steps has been described.
D-ribose by using the Baylis–Hillman reaction and ring-closing metathesis reactions as key
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Pericosine
Carbasugars
Baylis–Hillman reaction
Ring closing metathesis
Hoveyda–Grubbs catalyst
Pericosines A–E (Fig. 1) are a class of highly oxygenated cyclo-
hexenoid natural products.1 These compounds, which have been
isolated from sea hare aplysia kurodai, are found to be cytotoxic
metabolites of the fungus periconia byssoid OUPS-N133.1b,c Their
significant bioactivity such as selective growth inhibition against
the murine P 388 cell lines, and human cancer cell lines, inhibition
of protein kinase EGFR and human topoisomerase II are notewor-
thy.2 These multifunctional cyclohexanoid natural products that
contain several chiral centers, also regarded as carbasugars,3,4 have
been targets of many synthetic studies. These synthetic studies
involving the use of (i) benzene and its derivatives, and (ii) quinic
acid and shikmic acid have been reported.5 Besides this, a chemo-
enzymatic approach has also been reported.6 However, in some of
these syntheses of pericosines a stoichiometric amount of toxic os-
mium tetroxide has been utilized, along with the formation of
many unwanted side products. Hence, it is important that flexible
synthetic routes overcoming such drawbacks are sought.5a,b,6b
Recently we have reported7 the synthesis of pyrrolidine azasugar
analogues, by employing the Baylis–Hillman reaction and ring clos-
ing metathesis reactions as key steps, which are found to be moder-
ate glycosidase inhibitors. Later, a somewhat similar protocol was
utilized by others8 for the construction of carbacycles viz. (+)-
MK7607 8 and (+)-streptol 9.
as hybrids of
D
-galactose with 1-deoxynojirimycin analogues,12 and
carbasugars.13 This, coupled with the aspiration of exploring the
synthetic utility of ring-closing metathesis toward biologically
important molecules as glycosidase inhibitors,14 has led us to report
on the total syntheses of (+), (ꢀ)-pericosine B and (+), (ꢀ)-pericosine
C from commercially available D-ribose. Retrosynthetic analysis for
our approach is shown in Scheme 1 which indicates the implemen-
tation of ring closing metathesis on the Baylis–Hillman adduct 11,
which was identified as a common intermediate for both the iso-
mers. Adduct 11 in turn could be obtained from the primary alcohol
12 on oxidation followed by the Baylis–Hillman reaction in the pres-
ence of methyl acrylate. The primary alcohol 12 could be realized
from the corresponding hemi acetal 13 which in turn could be ob-
tained from commercially available
Our synthesis of pericosines emanated from the known hemiac-
etal 13 derived from
-ribose15 which was transformed into diol 16
(Scheme 2) through the sodium borohydride reduction in excellent
yield. Selective protection of the primary hydroxyl group 16 with
pivolyl chloride in the presence of pyridine gave the secondary
alcohol 17. Protection of the secondary hydroxyl group as the –
MOM ether with chloromethyl methyl ether (MOM-Cl) in the pres-
ence of N,N-diisopropylethylamine (DIPEA) gave the fully pro-
tected compound 18 in an 89% yield. Selective deprotection of
the pivolyl group in 18 with NaOMe led to the primary alcohol
12. Oxidation of 12 with CrO3/py in acetic anhydride furnished
the corresponding aldehyde. The crude aldehyde was found to be
rather unstable and hence it was immediately subjected to the
Baylis–Hillman reaction with methyl acrylate in the presence of
DABCO leading to compound 19 as an inseparable mixture of
D-ribose (Scheme 1).
D
We have been interested in developing newer methodologies9–11
and their applications en route to some useful synthons, synthesis of
N-glycopetides,11 and synthesis of novel carbohydrate entities such
⇑
Corresponding author. Tel.: +91 0512 259 7169; fax: +91 0512 259 7492.
E-mail address: vankar@iitk.ac.in (Y.D. Vankar).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.135

Y. S. Reddy et al. / Tetrahedron Letters 53 (2012) 132–136
133
OMe
OMe
OMe
OH
Cl
HO
HO
CO2Me
HO
HO
HO
CO2Me
CO2Me
HO
HO
CO2Me
HO
OH
OH
OH
(+)-Pericosine A
(+)-Pericosine C
(-)-Pericosine B
(+)-Pericosine B
1
3
2
4
Cl
OMe
CO2Me
HO
HO
CO2Me
HO
HO
CO2Me
MeO2C
Cl
O
OH
OH
OH
OH
HO
OH
OH
Pericosine E
(+)-Pericosine D
(-)-Pericosine C
6
7
5
OH
HO
OH
HO
HO
OH
OH
HO
OH
OH
(+)-MK7607
(+)-Streptol
8
9
Figure 1. Structures of (+), (ꢀ)-pericosines A–E and carbasugars.
CO2Me
CO2Me
MeO
HO
HO
HO
HO
OMOM
OMOM
O
O
O
O
OH
O
OMOM
O
OH
10
11
12
14
O
OH
OH
O
HO
O
HO
HO
O
O
O
O
OH
D-ribose
13
Scheme 1. Retrosynthetic analysis for the synthesis pericosines.
15
two diastereomers in 1:1 ratio. The presence of 10 olefinic protons
for both the diastereomers in the 1H NMR spectrum (d 6.35–5.21),
in addition to other data, confirmed the formation of the product.
The diene 19 upon ring closing metathesis in the presence of
Grubb’s second generation catalyst gave the expected carbasugar
skeleton in a 20% yield. However, ring-closing metathesis of 19
proceeded smoothly in the presence of 10 mol % of the Hoveyda–
Grubb’s second generation catalyst A to afford cyclic compounds
20 and 21 in an 86% yield as chromatographically separable enti-
ties. The chemical shifts of various protons in the 1H NMR spectra
of 20 and 21 were assigned using the COSY spectral data.16 In the
1H NMR spectrum of diastereomer 20, the disappearance of the
multiplet due to olefinic protons in the region d 6.35–5.21 and
the appearance of lone olefinic proton signal resonating at d 6.92
as a doublet with coupling constant J = 4.3 Hz were observed. Fur-
ther, one of the two allylic protons appeared at d 4.59 as a doublet
(J = 8.2 Hz), and the other one resonated at d 4.51 as a double dou-
blet (J = 3.6, 3.6 Hz) along with the rest of the protons appearing at
the expected chemical shifts confirmed its structure.
constant J = 5.5 Hz, and one of its allylic protons appeared at d
4.95 as a doublet (J = 3.3 Hz), while the other one resonated at d
4.57 as a double doublet (J = 5.5, 5.2 Hz) confirmed that the cycliza-
tion had occurred. Further, for compound 20 the HRMS spectrum
displayed the [M+H]+ 289.1288, calculated 289.1282 for the molec-
ular formula C13H21O7, whereas for the other compound 21 the
HRMS spectrum displayed the [M+Na]+ 311.1102, calculated
311.1101 for the molecular formula C13H20O7Na.
The stereochemistry of the newly generated stereocenter in
both the separated derivatives was deduced using the NOE spec-
tral analysis (Fig. 2). Thus, in an NOE experiment, irradiation of
the signal for H-7a at d 3.49 in the carbasugar derivative 20
led to the enhancement of the signal for H-4 at d 4.59 indicating
that H-7a is cis to H-4, thus concluding R configuration of the
newly generated center (C-4). Whereas, for the carbasugar deriv-
ative 21 irradiation of the signal for H-4 at d 4.95 led to no
enhancement in the signal for H-7a at d 4.05 indicating that
H-4 and H-7a are trans to each other confirming the stereochem-
istry at the newly generated center to be of S configuration.16
These absolute configurations at C-4 in both 20 and 21 are
shown in Figure 2 which were further confirmed by converting
In the 1H NMR spectrum of the other diastereomer 21, a lone ole-
finic proton signal resonated at d 7.02 as a doublet with coupling

134
Y. S. Reddy et al. / Tetrahedron Letters 53 (2012) 132–136
O
HO
NaBH4
OH
Piv-Cl
OH
Ref. 15
HO
PivO
D-Ribose
MeOH
Py, DCM
O
O
O
0 oC, 97%
O
O
O
C
0 oC-rt, 92%
13
16
17
i) CrO3, Py
OMOM
MOM-Cl
DIPEA,DCM
Ac2O, CH2Cl2, 0 o
OMOM
HO
NaOMe
MeOH
oC-rt, 95%
PivO
ii)
O
O
O
O
CO2Me
0
0
oC-rt, 89%
DABCO, DMF
12
18
N
N
Mes
Mes
MeO2C
HO
Cl
Ru
O
Grubb's cat. (A)
Cl
OMOM
20
21
Me
toluene, 110 o
86%
C
Me
O
O
Hoveyda-Grubbs Catalyst
2
nd Generation
(A)
19
Scheme 2. Synthesis of carbasugar derivatives 20 and 21.
protocol17a with mild and neutral methylating reagents such as
MeI in the presence of freshly prepared Ag2O did not show any
reaction toward this substrate. However, to our delight, addition
of a catalytic amount dimethyl sulfide to the above reaction mix-
ture17b worked well and gave the desired methylated product 22
in a 95% yield. Since the final step of our synthetic endeavor com-
prises a global deprotection of both acetal and MOM–ether, the
same was achieved with TFA in methanol to furnish the target
(+)-pericosine B 2 in an 81% yield.5a,6a
CO2Me
CO2Me
H
H
5
6
5
6
HO
H
H
H
4
4
H
HO
7a
7a
7
3a
7
3a
OMOM
OMOM
O
O
O
O
2
3
2
3
The physical and spectroscopic data of synthetic 2 were found
to be consistent with the reported values.5a,6a The HRMS spectrum
displayed the [M+Na]+ 241.0682, calculated 241.0683 for the
molecular formula C9H14O6Na.
20
Figure 2. NOE correlations for the compounds 20 and 21.
21
Likewise, the other isomer 21 (Scheme 3) was subjected to the
same set of reactions and conditions as applied earlier afforded 23
(91%) which was subsequently transformed into our next target 3
that is (+)-pericosine C in an 88% yield.5b,6a In essence, both the iso-
mers obtained during the Baylis–Hillman reaction were effectively
converted into two target compounds through the common syn-
thetic protocol.
them into known (+)-pericosine B 2 and (+)-Pericosine C 3 (vide
infra), respectively.
The hydroxy ester 20 was then taken up for the synthesis of (+)-
pericosine B. The selection of suitable methylation conditions for
compound 20 seemed to be a tricky one as the substrate contained
both acid and base sensitive functional groups. The methylation
CO2Me
CO2Me
CO2Me
HO
MeO
MeO
HO
TFA
Ag2O, MeI
OMOM
O
OMOM
O
MeOH
0 oC-rt, 81%
THF. Me2S
rt, 3h, 95%
OH
O
O
OH
2
20
22
CO2Me
(+)-pericosine B
CO2Me
CO2Me
HO
MeO
MeO
HO
Ag2O, MeI
TFA
OMOM
O
OMOM
THF. Me2S
rt, 3h, 91%
O
MeOH
OH
0 oC-rt, 88%
O
O
OH
3
21
23
(+)-pericosine C
Scheme 3. Synthesis of (+)-pericosine B 2 and (+)-pericosine C 3.

Y. S. Reddy et al. / Tetrahedron Letters 53 (2012) 132–136
135
Carbohydr. Chem. Biochem. 1990, 48, 21–90; (e) Suami, T. Top. Curr. Chem. 1990,
154, 257–283; (f) Berecibar, A.; Grandjean, C.; Siriwardena, A. Chem. Rev. 1999,
99, 779–844.
CO2Me
MeO
HO
5. (a) Usami, Y.; Suzuki, K.; Mizuki, K.; Ichikawa, H.; Arimoto, M. Org. Biomol.
Chem. 2009, 7, 315–318; (b) Usami, Y.; Ohsugi, M.; Mizuki, K.; Ichikawa, H.;
Arimoto, M. Org. Lett. 2009, 11, 2699–2701; (c) Usami, Y.; Mizuki, K.; Ichikawa,
H.; Arimoto, M. Tetrahedron: Asymmetry 2008, 19, 1461–1464; (d) Usami, Y.;
Takaoka, I.; Ichikawa, H.; Horibe, Y.; Tomiyama, S.; Ohtsuka, M.; Imanishi, Y.;
Arimoto, M. J. Org. Chem. 2007, 72, 6127–6134; (e) Usami, Y.; Ueda, Y. Synthesis
2007, 3219–3225; (f) Usami, Y.; Horibe, Y.; Takaoka, I.; Ichikawa, H.; Arimoto,
M. Synlett 2006, 1598–1600; (g) Usami, Y.; Ueda, Y. Chem. Lett. 2005, 34, 1062–
1063; (h) Usami, Y.; Hatsuno, C.; Yamamoto, H.; Tanabe, M.; Numata, A. Chem.
Pharm. Bull. 2005, 52, 1130–1133; (i) Fejes, Z.; Mándi, A.; Komáromi, I.; Bényei,
A.; Naesens, L.; Fenyvesi, F.; Szilágyi, L.; Herczegh, P. Tetrahedron 2009, 65,
8171–8175.
OH
OH
4
(-)-pericosine B
O
HO
Ref. 18
D-Ribose
CO2Me
O
MeO
HO
O
OH
15
6. (a) Boyd, D. R.; Sharma, N. D.; Acaru, C. A.; Malone, J. F.; O’Dowd, C. R.; Allen, C.
C. R.; Stevenson, P. J. Org. Lett. 2010, 12, 2206–2209; (b) Donohoe, T. J.; Blades,
K.; Helliwell, M.; Waring, M. J.; Newcombe, N. J. Tetrahedron Lett. 1998, 39,
8755–8758.
OH
5
(-)-pericosine C
7. Doddi, V. R.; Vankar, Y. D. Eur. J. Org. Chem. 2007, 5583–5589.
8. Krishna, P. R.; Kadiyala, R. R. Tetrahedron Lett. 2010, 51, 2586–2588.
9. (a) Reddy, Y. S.; John Pal, A. P.; Gupta, P.; Ansari, A. A.; Vankar, Y. D. J. Org. Chem.
2011, 76, 5972–5984; (b) Kancharla, P. K.; Reddy, Y. S.; Dharuman, S.; Vankar,
Y. D. J. Org. Chem. 2011, 76, 5832–5837; (c) John Pal, A. P.; Vankar, Y. D.
Tetrahedron Lett. 2010, 51, 2519–2524.
10. (a) Kancharla, P. K.; Vankar, Y. D. J. Org. Chem. 2010, 75, 8457–8464; (b) Rawal,
G. K.; Rani, S.; Kumari, N.; Vankar, Y. D. J. Org. Chem. 2009, 74, 5349–5355; (c)
Rawal, G. K.; Kumar, A.; Tawar, U.; Vankar, Y. D. Org. Lett. 2007, 9, 5171–5174.
11. Reddy, B. G.; Madhusudanan, K. P.; Vankar, Y. D. J. Org. Chem. 2004, 69, 2630–
2633.
12. (a) Kumar, A.; Rawal, G. K.; Vankar, Y. D. Tetrahedron 2008, 64, 2379–2390; (b)
Jayakanthan, K.; Vankar, Y. D. Tetrahedron Lett. 2006, 47, 8667–8671; (c) Reddy,
B. G.; Vankar, Y. D. Angew. Chem., Int. Ed. 2005, 44, 2001–2004. and references
cited therein.
13. (a) Gupta, P.; John Pal, A. P.; Reddy, Y. S.; Vankar, Y. D. Eur. J. Org. Chem. 2011,
1166–1175; (b) Reddy, Y. S.; Kadigachalam, P.; Doddi, V. R.; Vankar, Y. D.
Tetrahedron Lett. 2009, 50, 5827–5830; (c) Kancharla, P. K.; Doddi, V. R.;
Kokatla, H.; Vankar, Y. D. Tetrahedron Lett. 2009, 50, 6951–6954; (d) Doddi, V.
R.; Kumar, A.; Vankar, Y. D. Tetrahedron 2008, 64, 9117–9122; (e) Jayakanthan,
K.; Vankar, Y. D. Org. Lett. 2005, 7, 5441–5444.
Scheme 4. Synthesis of (ꢀ)-pericosine B 4 and (ꢀ)-pericosine C 5.
Similarly, (ꢀ)-pericosine B 4 and (ꢀ)-pericosine C 5 were also
synthesized (Scheme 4) following the same synthetic sequences
starting from D
-ribose derived hemi acetal 15.18 All the spectral
data of the intermediates as well as the final compounds viz.
(ꢀ)-pericosine B 8 and (ꢀ)-pericosine C 9 were in absolute match
with their enantiomers.
In summary, we have developed a simple and divergent route
for the synthesis of (+)-pericosine B and (+)-pericosine C along
with their enantiomers (ꢀ)-pericosine B and (ꢀ)-pericosine C via
Baylis–Hillmann reaction followed by ring-closing metathesis as
key steps. This approach toward the synthesis of functionalized
chiral cyclohexenes en route to different stereoisomers of perico-
sines is exemplary and might also be applicable to several other
pseudosugars and biologically important molecules.
14. (a) John Pal, A. P.; Gupta, P.; Reddy, Y. S.; Vankar, Y. D. Eur. J. Org. Chem. 2010,
6957–6966; (b) Kumari, N.; Reddy, B. G.; Vankar, Y. D. Eur. J. Org. Chem. 2008,
160–169.
15. Kim, W. H.; Kang, J. A.; Lee, H. R.; Park, A. Y.; Chun, P.; Lee, B.; Kim, J.; Kim, J. A.;
Jeong, L. S.; Moon, H. R. Carbohydr. Res. 2009, 344, 2317–2321. and references
therein.
Note added in Proof
16. Experimental data of selected compounds: (S)-1-((4S,5R)-5-(hydroxymethyl)-
For the latest approach to (+)-pericosine A and (+)-pericosine
B.19
2,2-dimethyl-1,3-dioxolan-4-yl)prop-2-en-1-ol (16): To
a stirred solution of
hemiacetal 13 (2.5 g, 13.42 mmol) in dry methanol (45 mL) at 0 °C was added
NaBH4 (1.27 g, 33.56 mmol) portion wise. The reaction mixture was allowed to
stir for 30 min and then quenched by the addition of saturated NH4Cl solution
(20 mL). Methanol was removed in vacuo, and the reaction mixture was
extracted with CH2Cl2 (3 ꢁ 25 mL). The combined organic extracts were
washed with water, brine, dried over Na2SO4 and the solvent was removed
to obtain the crude alcohol 16 which was purified by column chromatography.
Acknowledgments
We thank the Department of Science and Technology, New
Delhi, for J.C. Bose National Fellowship (JCB/SR/S2/JCB-26/2010)
to Y.D.V. and the Council of Scientific and Industrial Research,
New Delhi, for financial support [Grant No. 01(2298)/09/EMR-II].
Y.S.R. thanks the Council of Scientific Industrial Research, New
Delhi, for a Senior Research Fellowship.
Yield: 97% (2.43 g), Rf: 0.2 (hexane/ethyl acetate, 7:3), yellow liquid, ½a D28
ꢂ
ꢀ32.35 (c 1.7, CH2Cl2) IR(neat)
m
max/cmꢀ1: 3392, 2987, 2937, 2888, 1645, 1456,
1382, 1244, 1220, 1167, 1132, 1073, 1047, 995, 928, 884, 852. 1H NMR
(500 MHz, CDCl3): d 6.01–5.95 (m, 1H), 5.37 (dd, 1H, J = 17.4 Hz, 17.1 Hz), 5.26
(dd, 1H, J = 10.7 Hz, 10.3 Hz), 4.30ꢀ4.27 (m, 2H), 4.05–4.01 (m, 1H), 3.87–3.82
(m, 1H), 3.78-3.73 (m, 1H), 3.55 (br s, 1H), 3.41 (br s, 1H), 3.41 (br s, 1H), 1.41
(br s, 3H), 1.33 (br s, 3H). 13C NMR (125 MHz, CDCl3): d 137.5, 116.9, 108.6,
79.6, 77.3, 70.7, 60.8, 27.8, 25.3. HRMS (ESI): calcd for C9H17O4 [M+H]+
189.1121; found 189.1129.
Supplementary data
((4R,5S)-5-((S)-1-hydroxyallyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl pivalate
(17): To a solution of diol 16 (1.5 g, 7.96 mmol) in CH2Cl2 (30 mL) was added
pyridine (946 mg, 11.95 mmol) and pivolyl chloride (1.15 g, 9.56 mmol) at 0 °C.
A catalytic amount of 4-dimethylaminopyridine (DMAP) was also added. The
mixture was stirred at ambient temperature for 18 h and then diluted with
CH2Cl2 (30 mL). The organic layer was washed with aq 5% HCl (30 mL),
saturated aqueous NaHCO3 (30 mL), and brine (50 mL), dried with Na2SO4,
filtered, and concentrated in vacuo to obtain the crude alcohol 17 which was
submitted to column chromatography. Yield: 92% (2.0 g), Rf: 0.6 (hexane/ethyl
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.10.135.
References and notes
1. (a) Usami, Y.; Mizuki, K. J. Nat. Prod. 2011, 74, 877–881; (b) Yamada, T.; Iritani,
M.; Ohishi, H.; Tanaka, K.; Doi, M.; Minoura, K.; Numata, A. Org. Biomol. Chem.
2007, 5, 3979–3986; (c) Numata, A.; Iritani, M.; Yamada, T.; Minoura, K.;
Matsumura, E.; Yamori, T.; Tsuruo, T. Tetrahedron Lett. 1997, 38, 8215–8218.
2. Usami, Y.; Ichikawa, H.; Arimoto, M. Int. J. Mol. Sci. 2008, 9, 401–421.
3. (a) Mehta, G.; Sen, S. Tetrahedron Lett. 2010, 51, 503–507; (b) Mehta, G.; Roy, S.;
Davis, R. A. Tetrahedron Lett. 2008, 49, 5162–5164; (c) Arjona, O.; Gomez, A. M.;
Lopez, J. C.; Plumet, J. Chem. Rev. 2007, 107, 1919–2036; (d) Alibes, R.; Bayon, P.;
March, P.; Figueredo, M.; Font, J.; Marjanet, G. Org. Lett. 2006, 8, 1617–1620; (e)
Sanchez-Abella, L.; Fernandez, S.; Armesto, N.; Ferrero, M.; Gotor, V. J. Org.
Chem. 2006, 71, 5396–5399.
acetate, 7:3), yellow liquid, ½a D28
ꢂ
+9.09 (c 1.65, CH2Cl2), IR(neat) m :
max/cmꢀ1
3450, 2983, 2936, 1730, 1644, 1481, 1460, 1399, 1372, 1285, 1220, 1164, 1081,
1036, 994, 927, 869, 850, 771. 1H NMR (500 MHz, CDCl3): d 6.03–5.96 (m, 1H),
5.37 (dd, 1H, J = 17.4 Hz, 17.1 Hz), 5.26 (dd, 1H, J = 10.4 Hz, 10.7 Hz), 4.42–4.35
(m, 2H), 4.27–4.21 (m, 2H), 4.04–4.01 (m, 1H), 2.14 (d, 1H, J = 3.9 Hz), 1.44 (br
13
s, 3H), 1.34 (br s, 3H), 1.20 (br s, 9H).
C NMR (125 MHz, CDCl3): d 178.4,
137.6, 116.9, 109.0, 79.2, 75.6, 70.9, 63.3, 38.8, 27.7, 27.2, 25.4. HRMS (ESI):
calcd For C14H24 NaO5 [M+Na]+ 295.1516; found 295.1529.
((4R,5S)-5-((S)-1-(Methoxymethoxy)allyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl
pivalate (18): To
a solution of secondary hydroxyl compound 17 (1.35 g,
4. (a) Newman, D. J.; Cragg, G. M. Curr. Drug Targets 2006, 7, 279–304; (b) Fenical,
W.; Jensen, P. R. Nat. Chem. Biol. 2006, 2, 666–673; For reviews, see: (c) Suami,
T. Pure Appl. Chem. 1987, 59, 1509–1520; (d) Suami, T.; Ogawa, S. Adv.
4.95 mmol) in CH2Cl2 (25 mL) was added N,N-diisopropylethylamine (DIEPA)
(1.29 mL, 7.43 mmol) and MOM-Cl (961 mg, 5.94 mmol) at 0 °C followed by
addition of a catalytic amount of DMAP. The mixture was stirred at ambient

136
Y. S. Reddy et al. / Tetrahedron Letters 53 (2012) 132–136
temperature for 24 h and then diluted with CH2Cl2 (25 mL). The organic layer
–OH), 3.79 (s, 3H, –OMe), 3.49 (dd, 1H, J = 3.6 Hz, 3.6 Hz, H-7a), 3.38 (s, 3H, –
OMe), 1.46 (br s, 6H, –OC(CH3)2). 13C NMR (125 MHz, CDCl3): d 166.7, 136.6,
134.7, 111.9, 96.8, 76.0, 75.8, 70.8, 68.1, 55.7, 52.5, 27.1, 26.6. HRMS (ESI): calcd
for C13H21O7 [M+H]+ 289.1282; found 289.1288.
was washed, saturated with aqueous NaHCO3 (30 mL), and brine (50 mL), dried
with Na2SO4, filtered, and concentrated in vacuo to obtain the crude alcohol 18
which was purified by column chromatography. Yield: 89% (1.4 g), Rf: 0.45
(hexane/ethyl acetate, 9:1), ½a D28
ꢂ
ꢀ74.66, (c 0.75, CH2Cl2), IR(neat)
m
max/cmꢀ1
:
(3aR,4S,7S,7aS)-Methyl
4-hydroxy-7-(methoxymethoxy)-2,2-dimethyl-3a,4,7,7a-
3082, 2982, 2936, 2826, 1730, 1645, 1481, 1460, 1398, 1380, 1371, 1284, 1244,
1218, 1160, 1082, 1033, 990, 923, 867, 850, 796. 1H NMR (500 MHz, CDCl3): d
5.77–5.71 (m, 1H), 5.38 (dd, 1H, J = 10.4 Hz, 10.3 Hz), 5.32 (dd, 1H, J = 17.4 Hz,
tetrahydrobenzo[d][1,3]dioxole-5-carboxylate (21): Colorless liquid, Yield: 44%
(52 mg), Rf: 0.21 (4:1, hexane/ethyl acetate), ½a D28
ꢂ
+126.66 (c 0.6, CH2Cl2), IR
(neat) m
max/cmꢀ1: 3458, 2987, 2931, 2851, 1723, 1631, 1439, 1372, 1275, 1237,
18.0 Hz), 4.70 (d, 1H, J = 6.7 Hz), 4.43–4.37 (m, 2H), 4.22–4.13 (m, 3H), 3.18 (s,
1170, 1152, 1126, 1103, 1083, 1048, 1014, 969, 932, 919, 886, 850, 796, 772,
742. 1H NMR (500 MHz, CDCl3): d 7.02 (d, 1H, J = 5.5 Hz, H-6), 4.95 (d, 1H,
J = 3.3 Hz, H-4), 4.87 (d, 1H, J = 6.4 Hz, H-9), 4.67 (d, 1H, J = 6.7 Hz, H-90), 4.57
(dd, 1H, J = 5.5 Hz, 5.2 Hz, H-7), 4.05 (dd, 1H, J = 3.6 Hz, 3.7 Hz, H-7a), 3.97 (dd,
1H, J = 3.6 Hz, 3.6 Hz, H-3a), 3.80 (s, 3H, –OMe), 3.38 (s, 3H, –OMe), 2.59 (br s,
1H, –OH), 1.48 (s, 3H, –OC(CH3)), 1.47 (s, 3H, –OC(CH3)). 13C NMR (125 MHz,
CDCl3): d 166.3, 138.8, 133.5, 111.3, 97.0, 73.7, 72.9, 68.1, 64.1, 55.7, 52.5, 26.8,
26.8. HRMS (ESI): calcd for C13H20NaO7 [M+Na]+ 311.1101; found 311.1102.
(3aR,4R,7S,7aS)-Methyl 4-methoxy-7-(methoxymethoxy)-2,2-di-methyl-3a,4,7,7a-
tetrahydrobenzo[d][1,3]dioxole-5-carboxylate (22): Compound 20 (30 mg,
0.1 mmol) was dissolved in THF (2 mL) and methyl iodide (222 mg,
1.56 mmol). Silver(I)oxide (232 mg, 1.0 mmol) was added as well as one drop
of dimethyl sulfide as a catalyst. The flask was wrapped with aluminium foil to
exclude daylight. The mixture was stirred for 3 h. After filtration over a pad of
celite to remove the silver salts a column chromatography was performed to
obtain 30 mg (95%) of 22 as a colorless oil. Rf: 0.5 (4:1, hexane/ethyl acetate),
13
3H), 1.45 (s, 3H), 1.34 (s, 3H), 1.21 (br s, 9H).
C NMR (125 MHz, CDCl3): d
178.5, 134.7, 120.7, 108.9, 93.8, 78.1, 75.8, 75.5, 63.4, 56.5, 38.8, 27.5, 27.2,
25.3. HRMS (ESI): calcd for C16H28NaO6 [M+Na]+ 339.1778; found 339.1781.
((4R,5S)-5-((S)-1-(Methoxymethoxy)allyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol
(12): To a solution of compound 18 (1.0 g, 3.16 mmol) in dry MeOH (20 mL) at
0 °C was added a catalytic amount of NaOMe. The mixture was stirred for 24 h at
room temperature and after completion of the reaction (TLC monitoring) MeOH
was evaporated, extracted with EtOAc (3 ꢁ 20 mL) and the organic layer washed
with water and brine. Evaporation of the solvent followed by purification using
SiO2 column chromatography gave 12. Yield: 95% (700 mg), colorless liquid. Rf:
0.20 (hexane/ethyl acetate, 2:8), ½a D28
ꢂ
ꢀ67.27 (c 0.55, CH2Cl2); IR(neat) mmax
/
cmꢀ1: 3486, 3081, 2987, 2938, 2893, 2826, 1644, 1455, 1406, 1381, 1371, 1246,
1218, 1156, 1033, 921, 886, 847, 796. 1H NMR (500 MHz, CDCl3): d 5.76–5.69 (m,
1H), 5.38 (d, 1H, J = 10.4 Hz, 10.3 Hz), 5.33 (dd, 1H, J = 17.1 Hz, 16.2 Hz), 4.72 (d,
1H, J = 6.7 Hz), 4.56 (d, 1H, J = 6.4 Hz), 4.30 (dd, 1H, J = 11.6 Hz, 11.9 Hz), 4.11 (dd,
1H, J = 7.9 Hz, 7.6 Hz), 3.83–3.76 (m, 2H), 3.40 (br s, 3H), 2.67 (t, 1H, J = 7.0 Hz),
1.43 (br s, 3H), 1.34 (br s, 3H). 13C NMR (125 MHz, CDCl3): d 134.6, 120.7, 108.6,
94.1, 78.1, 77.8, 76.0, 61.1, 56.5, 27.7, 25.4. HRMS (ESI): calcd for C11H20NaO5
[M+Na]+ 255.1203; found 255.1209.
½ ꢂ +120.0 (c 0.5, CH2Cl2) IR (neat) m
a D28 max/cmꢀ1: 2987, 2935, 1730, 1634, 1438,
1382, 1371, 1317, 1275, 1246, 1194, 1170, 1151, 1103, 1026, 973, 919, 886,
846, 793, 758. 1H NMR (500 MHz, CDCl3): d 6.66–6.65 (m, 1H), 4.83 (d, 1H,
J = 6.8 Hz), 4.67 (d, 1H, J = 6.6 Hz), 4.45 (dd, 1H, J = 3.4 Hz, 3.4 Hz), 4.20–4.18
(m, 1H), 4.13–4.09 (m, 1H), 3.77 (s, 3H), 3.54 (s, 3H), 3.44 (dd, 1H, J = 3.4 Hz,
3.4 Hz), 3.37 (s, 3H), 1.45 (br s, 6H). 13C NMR (125 MHz, CDCl3): d 166.6, 136.2,
134.2, 111.4, 96.7, 78.9, 76.2, 68.0, 59.1, 55.6, 52.2, 27.2, 26.7. HRMS (ESI): calcd
for C14H23O7 [M+H]+ 303.1438; found 303.1440.
(3aR,4S,7S,7aS)-Methyl 4-methoxy-7-(methoxymethoxy)-2,2-dimethyl-3a,4,7,7a-
tetrahydrobenzo[d][1,3]dioxole-5-carboxylate (23): Compound 23 (19 mg, 91%
yield) was obtained as a viscous liquid from 21 (20 mg, 0.07 mmol) using the
same procedure which was used to obtain 22. Rf: 0.5 (hexane/ethyl acetate,
Methyl
2-(hydroxy((4R,5S)-5-((S)-1-(methoxymethoxy)allyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)methyl)acrylate (19): In a two neck round bottomed dry flask,
was added CrO3 (207 mg, 2.06 mmol), under N2 atmosphere, containing
anhydrous CH2Cl2 (5 mL), and cooled to 0 °C. Anhydrous pyridine (633 mg,
8.0 mmol) and Ac2O (425 mg, 4.16 mmol) were added followed by slow addition
of a solution of alcohol 12 (300 mg, 1.29 mmol) in CH2Cl2 (5 mL) to the reaction
mixture over 5 min. After 20 min the black solution was poured into EtOAc
(12 mL) and the mixture was filtered through silica and washed with EtOAc to
get a crude aldehyde. To a solution of this crude aldehyde in dry DMF (10 mL),
DABCO (135 mg, 1.2 mmol) and methyl acrylate (333 mg, 3.87 mmol) were
added and stirred for 24 h at room temperature. After the completion of reaction
(TLC), diethyl ether and water were added to the reaction mixture and extracted
with diethyl ether (3 ꢁ 15 mL). The extract was washed with brine (25 mL),
dried (Na2SO4), and concentrated under reduced pressure to afford a residue,
which was purified by column chromatography to furnish the corresponding
Baylis–Hillman adduct 19 (350 mg, 86% (from two steps)) as an inseparable
mixture of two diastereomers in 1:1 ratio. Rf: 0.3 (hexane/ethyl acetate, 9:1),
4:1), ½a 2D8
ꢂ
+113.3 (c 0.3, CH2Cl2); IR (neat) m
max/cmꢀ1: 2986, 2932, 2827,
1724, 1633, 1438, 1371, 1275, 1237, 1194, 1171, 1152, 1123, 1104, 1081,
1052, 1030, 968, 940, 919, 854, 798, 768, 741. 1H NMR (500 MHz, CDCl3): d
6.95 (d, 1H, J = 5.2 Hz), 4.87 (d, 1H, J = 6.7 Hz), 4.66 (d, 1H, J = 6.7 Hz), 4.56–
4.55 (m, 1H), 4.07 (dd, 1H, J = 3.9 Hz, 3.9 Hz), 3.98 (dd, 1H, J = 3.3 Hz, 3.3 Hz),
3.79 (s, 3H), 3.58 (s, 3H), 3.38 (s, 3H), 1.47 (s, 3H), 1.45 (s, 3H). 13C NMR
(125 MHz, CDCl3): d 166.2, 138.3, 133.0, 111.0, 97.0, 74.9, 73.3, 73.1, 68.2,
60.6, 55.7, 52.4, 26.8, 26.7. HRMS (ESI): calcd for
325.1258; found 325.1260.
C
14H22NaO7 [M+Na]+
½
a 2D8
ꢂ
+37.6 (c 1.25, CH2Cl2); IR (neat)
1719, 1631, 1440, 1381, 1372, 1248, 1214, 1153, 1100, 1031, 920, 865, 819,
748 cmꢀ1 1H NMR (500 MHz, CDCl3): d 6.35 (br s, 2H), 5.97-5.94 (m, 2H), 5.82–
m
max/cmꢀ1: 3463, 2988, 2937, 2896, 2826,
(3S,4S,5S,6R)-Methyl 3,4,5-trihydroxy-6-methoxycyclohex-1-ene-carboxylate (2):
To a solution of 22 (12 mg, 0.03 mmol) in methanol (1 mL) cooled to 0 °C was
added trifluroacetic acid (1 mL) and the mixture stirred for 24 h at room
temperature. After completion of the reaction (TLC), the solvent was removed
under reduced pressure directly to give a crude product which was purified
by column chromatography to afford pure compound 2 (7 mg, 81%) as a
.
5.75 (m, 2H), 5.39–5.21 (m, 4H), 4.72–4.69 (m, 2H), 4.60–4.56 (m, 2H), 4.52 (d,
2H, J = 6.7 Hz), 4.18 (dd, 1H, J = 7.9 Hz, 7.9 Hz), 4.14–4.06 (m, 4H), 3.99 (dd, 1H,
J = 8.5 Hz, 8.2 Hz), 3.75 (br s, 6H), 3.36 (s, 3H), 3.35 (s, 3H), 3.31 (d, 1H, J = 4.9 Hz),
2.89 (d, 1H, J = 9.2 Hz), 1.43 (s, 3H), 1.40 (s, 3H), 1.37 (br s, 6H). 13C NMR
(125 MHz, CDCl3): d 166.5, 166.5, 140.0, 138.4, 133.6, 133.4, 127.3, 126.5, 121.4,
120.8, 110.0, 110.0, 93.9, 90.3, 79.6, 79.4, 79.4, 79.1, 77.6, 77.3, 71.5, 69.3, 55.8,
55.7, 52.0, 52.0, 27.2–27.1 (m). HRMS (ESI): calcd for C15H24NaO7 [M+Na]+
339.1414; found 339.1420.
colourless liquid. Rf: 0.5 (ethyl acetate/methanol, 4:1), ½a D28
ꢂ
+48.88 (c 0.35,
EtOH). 1H NMR (500 MHz, acetone-d6): d 6.70 (d, 1H, J = 3.8 Hz, H-2),4.48 (br
s, 1H, –OH), 4.27 (br s, 1H, H-6), 4.09–4.06 (m, 2H, H-3, –OH), 3.94–3.93 (m,
1H, H-4), 3.78–3.74 (m, 1H, H-5), 3.70 (s, 3H, COOMe), 3.65–3.61 (m, 1H, –
OH), 3.47 (s, 3H, –OMe). 13C NMR (125 MHz, acetone-d6): d 166.4, 138.4,
131.5, 78.4, 70.3, 69.6, 65.8, 58.9, 51.1. HRMS (ESI): calcd for C9H14NaO6
[M+Na]+ 241.0683; found 241.0682.
(3aR,7S,7aS)-Methyl
4-hydroxy-7-(methoxymethoxy)-2,2-dimethyl-3a,4,7,7a-
tetrahydrobenzo[d][1,3]dioxole-5-carboxylate:
To a stirred solution of compound 19 (150 mg, 0.47 mmol) in dry CH2Cl2 (5 mL)
at room temperature was added Hoveyda–Grubb’s second generation catalyst A
(10 mol %, 29.7 mg). The reaction mixture was refluxed for 30 h and after
completion of the reaction, the solvent was evaporated under reduced pressure
and the crude product was purified by column chromatography to give
compound 20 and 21 (117 mg, 86% combined yield).
(3S,4S,5S,6S)-Methyl 3,4,5-trihydroxy-6-methoxycyclohex-1-enecarboxylate (3):
Compound 3 (5 mg, 88% yield) was obtained as a viscous liquid from 23
(8 mg, 0.02 mmol) using the same procedure which was used to obtain 2. Rf:
0.5 (ethyl acetate/methanol, 4:1) ½ ꢂ
a 2D8 +32.0 (c 0.25, EtOH). 1H NMR
(500 MHz, acetone-d6): d 6.67 (br s, 1H, H-2), 4.40–4.36 (m, 1H, H-3), 4.20
(br s, 1H, H-6), 3.98–3.92 (m, 2H, H-4, H-5), 3.71 (s, 3H, COOMe), 3.46 (s, 3H,
–OMe). 13C NMR (125 MHz, acetone-d6): d 166.5, 139.1, 131.4, 75.5, 69.3,
68.9, 65.7, 59.2, 51.2. HRMS (ESI): calcd for C9H14NaO6 [M+Na]+ 241.0683;
found 241.0683.
(3aR,4R,7S,7aS)-Methyl 4-hydroxy-7-(methoxymethoxy)-2,2-di-methyl-3a,4,7,7a-
tetrahydrobenzo[d][1,3]dioxole-5-carboxylate (20): Red brown liquid. Yield: 56%
(65 mg), Rf: 0.22 (4:1 hexane/ethyl acetate); ½a D28
ꢂ
+95.0 (c 0.6, CH2Cl2); IR (neat)
m
max/cmꢀ1: 3473, 3057, 2988, 2954, 2917, 1723, 1629, 1439, 1373, 1246, 1171,
17. (a) Greene, A. E.; Drian, C. L.; Crabbe, P. J. Am. Chem. Soc. 1980, 102, 7583–7584;
(b) Werz, D. B.; Seeberger, P. H. Angew. Chem., Int. Ed. 2005, 44, 6315–6318.
18. (a) Kaliappan, K. P.; Ravikumar, V.; Pujari, A. J. Chem. Sci. 2008, 120, 205–216;
(b) Ramana, G. V.; Rao, B. V. Tetrahedron Lett. 2005, 46, 3049–3051.
19. Tripathi, S.; Shaikh, A. C.; Chen, C. Org. Biomol. Chem. 2011, 9, 7306–7308.
1150, 1106, 1068, 1039, 969, 952, 918, 884, 843, 791, 760, 737, 702, 621, 518. 1
H
NMR (500 MHz, CDCl3): d 6.92 (d, 1H, J = 4.3 Hz, H-6), 4.85 (d, 1H, J = 6.7 Hz, H-
9), 4.67 (d, 1H, J = 6.7 Hz, H-90), 4.59 (d, 1H, J = 8.2 Hz, H-4), 4.51 (dd,, J = 3.6 Hz,
3.6 Hz, 1H, H-7), 4.12 (dd, 1H, J = 8.2 Hz, 8.2 Hz, H-3a), 3.83 (d, 1H, J = 1.8 Hz,