Densely functionalized chiral pyrroles from endocyclic, exocyclic, and acyclic vinyl sulfone-modified carbohydrates

Article abstract of DOI:10.1021/jo801948m

A wide range of vinyl sulfone-modified carbohydrates have been prepared as starting materials for the synthesis of polysubstituted chiral pyrroles. All these vinyl sulfones reacted efficiently with ethylisocy-anoacetate to generate a plethora of new pyrro

Full text of DOI:10.1021/jo801948m

Densely Functionalized Chiral Pyrroles from Endocyclic, Exocyclic,
and Acyclic Vinyl Sulfone-Modified Carbohydrates
Rahul Bhattacharya, Ananta Kumar Atta, Debanjana Dey, and Tanmaya Pathak*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
tpathak@chem.iitkgp.ernet.in
ReceiVed September 4, 2008
A wide range of vinyl sulfone-modified carbohydrates have been prepared as starting materials for the
synthesis of polysubstituted chiral pyrroles. All these vinyl sulfones reacted efficiently with ethylisocy-
anoacetate to generate a plethora of new pyrrole derivatives. Furanosyl rings opened up during pyrrole
synthesis, and pyranosyl rings were opened up by reacting the pyrrole with POCl3/DMF. This paper also
reports one of the most efficient and practical routes for the synthesis of ꢀ-substituted pyrroles.
Introduction
products, designing of a general and practical method for the
synthesis of ꢀ-substituted pyrroles still remains a difficult
challenge.
Pyrrole-containing compounds play crucial roles in nature.1
Substituted pyrroles are important for research in pharmaceutical
and material sciences.2 Although a variety of synthetic ap-
proaches for the synthesis of pyrroles have been developed over
the years, a perusal of the literature reveals that even now the
synthesis of highly functionalized pyrroles remains a synthetic
challenge in terms of regioselectivity and chemoselectivity.3
Moreover, synthesis of ꢀ-substituted pyrroles was reported to
be particularly difficult because the direct alkylation or acylation
of pyrroles produced the desired products as minor components.
Although methods using the directing effects of N-protecting
groups or permanent R-substituents did produce the ꢀ-substituted
Conjugate addition of the anion generated from an isocy-
anoacetate to vinyl sulfones was put forward as a methodology
for the synthesis of pyrrole-2-esters.4 Since the strategy was
crucially dependent on the availability of functionalized vinyl
sulfones, highly specialized methods were devised in the past
decade for the synthesis of the derivatized vinyl sulfones.3-6
Although these vinyl sulfones were reacted with isocyanoac-
etates for the synthesis of pyrroles, the strategy stagnated over
the years for the nonavailability of straightforward and general
(4) Halazy, S.; Magnus, P. Tetrahedron Lett. 1984, 25, 1421.
(5) (a) Finikova, O. S.; Cheprakov, A. V.; Vinogradov, S. A. J. Org. Chem.
2005, 70, 9562. (b) Finikova, O. S.; Cheprakov, A. V.; Beletskaya, I. P.; Carroll,
P. J.; Vinogradov, S. A. J. Org. Chem. 2004, 69, 522. (c) Hwang, S. H.; Kurth,
M. J. J. Org. Chem. 2002, 67, 6564. (d) Abel, Y.; Haake, E.; Haake, G.; Schmidt,
W.; Struve, D.; Walter, A.; Montforts, F. P. HelV. Chim. Acta 1998, 81, 1978.
(e) Sumi, K.; Di Fabio, R.; Hanessian, S. Tetrahedron Lett. 1992, 33, 749. (f)
Padwa, A.; Norman, B. H. J. Org. Chem. 1990, 55, 4801.
(1) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell
Publishing: Cambridge, MA, 2003; pp 237-272.
(2) Chiba, S.; Wang, Y.-F.; Lapointe, G.; Narasaka, K. Org. Lett. 2008, 10,
313, and references cited therein.
(3) For reviews on pyrroles, see: (a) Ono, N. Heterocycles 2008, 75, 243.
(b) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F. Chem. ReV. 2008, 108, 264. (c)
Schmuck, C.; Rupprecht, D. Synthesis 2007, 20, 3095.
(6) (a) Uno, H.; Sahara, Y.; Takiue, T. Tetrahedron Lett. 2007, 48, 7825.
(b) Okujima, T.; Komobuchi, N.; Uno, H.; Ono, N. Heterocycles 2006, 67, 255.
(c) Cheng, W.-C.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem. 2001, 66, 5528.
10.1021/jo801948m CCC: $40.75
Published on Web 12/10/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 669–674 669

Bhattacharya et al.
TABLE 1. Vinyl Sulfone-Modified Carbohydrates as Precursors of
Densely Functionalized Chiral Pyrroles
methodologies for the synthesis of polysubstituted vinyl sul-
fones. A detailed analysis of these synthetic strategies revealed
that virtually all vinyl sulfones as starting materials for pyrroles
were derived from either symmetrical olefins via the addition
of PhSCl across the double bond5 or methods having no
potential for generating regioisomers.6 The serious shortcomings
of currently available methods for the synthesis of polysubsti-
tuted pyrroles were compounded7 by the fact that strategies for
the synthesis of pyrroles attached to chiral moieties are virtually
nonexistent.8 The usefulness of such chirally substituted pyrroles
in biological and material sciences can be studied only after
suitable methodologies are available for their synthesis in
relatively large amounts.
Results and Discussion
We opined that the utility of the powerful strategy used in vinyl
sulfone-mediated pyrrole synthesis can be immensely increased if
the substituted vinyl sulfones are synthesized through regiocon-
trolled routes. We observed that the C-S bond formation in the
synthesis of furanosyl and pyranosyl thiosugars is regiocontrolled,
and therefore the orientation of the vinyl sulfone group derived
from these thiosugars in the required vinyl sulfone-modified
carbohydrates is predefined.9 However, C-S bond formation in
exocyclic and acyclic sugar can also be made regiocontrolled by
suitably incorporating a leaving group or an epoxide ring. We
opined that vinyl sulfones derived from carbohydrates would act
as excellent and efficient acceptors for the carbanion generated from
ethylisocyanoacetate. Moreover, the inbuilt chiral environments of
the sugar residue would be automatically transferred to the newly
synthesized pyrroles. Therefore, we selected the endocyclic,
exocyclic, and acyclic vinyl sulfone-modified carbohydrates 1-8,
9, 10, 11, and 12, respectively, as substrates for the synthesis of
pyrroles (Table 1).
For the synthesis of endocyclic vinyl sulfone-modified
carbohydrates 1-8, C-S bonds were formed by opening an
epoxide in a regioselective fashion or by displacing a suitably
designed sulfonate ester.9 The exocyclic vinyl sulfone-modified
carbohydrate 6-C-tolysulfonyl-hex-5-enofuranoside 9 was also
obtained by reacting a 5,6-O-anhydro derivative with tolyl
thiol.10 For the synthesis of 5-C-tolysulfonyl-hex-5-enofurano-
side 10, the regioisomer of 9, the fully protected mesylate 1311
was treated with tolylthiol/NaOMe followed by aq. acetic acid
to obtain the sulfide 14. The sulfide was oxidized with MMPP
to the sulfone 15, which on treatment with mesyl chloride in
pyridine afforded the desired vinyl sulfone-modified carbohy-
drate 10 (Scheme 1).
SCHEME 1. Synthesis of Exo-Cyclic Vinyl Sulfone
We then turned our attention to the synthesis of the acyclic
vinyl sulfone 11 and the acyclic bisvinyl sulfone 12. Thus the
epoxide ring of an easily available tetrosyl epoxide 1612 was
regioselectively opened with the sulfur nucleophile to obtain
(7) “. .even 150 years after its isolation and synthesis, and more than 100
years after the classical pyrrole syntheses were developed, the synthesis of highly
substituted pyrroles is anything but straightforward.”3c
(8) There are scant reports on the synthesis of sugar linked pyrroles. In these
cases the aldehydo group of sugar molecule was directly reacted with pyrrole,
see: Yadav, J. S.; Reddy, B. V. Subba; Satheesh, G. Tetrahedron Lett. 2004, 45,
3673. Casiraghi, G.; Cornia, M.; Zanardi, F.; Rassu, G.; Ragg, E.; Bortolini, R.
J. Org. Chem. 1994, 59, 1801.
the alcohol 17. Oxidation of the sulfide 17, followed by one-
pot mesylation of the sulfone 18 and the elimination of sulfonic
acid, afforded the acyclic vinyl sulfone 11 (Scheme 2). The
synthesis of the bisvinyl sulfone 12 started from the known
ditosylate 19 derived from mannitol.13 The ditosylate derivative
19, on treatment with tolylthiol/TMG, generated the bissulfide
20. Oxidation of the bissulfide 20 afforded the bissulfone 21.
(9) Pathak, T. Tetrahedron. 2008, 64, 3605.
(10) Das, I.; Pal, T. K.; Suresh, C. G.; Pathak, T. J. Org. Chem. 2007, 72,
5523.
(11) Saeki, H.; Iwashige, T.; Ohki, E. Chem. Pharm. Bull. 1968, 16, 1040.
(12) Abushanab, E.; Vemishetti, P.; Leiby, R. W.; Singh, H. K.; Mikkilineni,
A. B.; Wu, D. C. J.; Saibaba, R.; Panzica, R. P. J. Org. Chem. 1988, 53, 2598.
(13) Le Merrer, Y.; Dureault, A.; Greck, C.; Micas, L. D.; Gravier, C.;
Depezay, J. C. Heterocycles 1987, 25, 541.
670 J. Org. Chem. Vol. 74, No. 2, 2009

Densely Functionalized Chiral Pyrroles
TABLE 2. Chiral Pyrroles from Vinyl Sulfone-Modified
Carbohydrates
SCHEME 2. Synthesis of Acyclic Vinyl Sulfone
SCHEME 3. Synthesis of Acyclic Bisvinyl Sulfone
Mesylation of the sulfone 21 in pyridine and concomitant
elimination of sulfonic acid afforded the acyclic bisvinyl sulfone
12 (Scheme 3).
All vinyl sulfones were treated with ethyl isocyanoacetate in
t
the presence of BuOK in dry THF at the reflux temperature
for 5 h to afford clean products. The results and the yields are
summarized in Table 2. The conversion is usually efficient with
the yields varying between 70 and 90%. Interestingly in the
case of furanosyl analogues 6-8, the sugar ring opened up in
situ to afford three different trisubstituted pyrroles 27-29,
respectively.
SCHEME 4. Reactions of Pyranosyl Derivatives of Pyrroles
with POCl3/DMF
Although this serendipitous reaction fulfilled our requirement
for opening the furanosyl sugar rings to afford polysubstituted
pyrroles 27-29, we continued to search for a reaction condition
for opening the pyranosyl rings of 22-26. We attempted several
reaction conditions for opening the sugar ring, and in almost
all cases, either the unreacted starting materials or the breakdown
products was obtained. To our surprise, while scanning reaction
conditions for the formylation of the pyrrole rings, we observed
that the POCl3 ·DMF complex smoothly opened the pyranosyl
rings of 22 and 23 to afford the trisubstituted pyrroles 34 and
35, respectively, in high yields (Scheme 4). Peaks ranging
between δ 9.96-10.87 (1H NMR) and δ 187.0-188.9 (13C
NMR) confirmed the presence of a free -CHO group in
compounds 27-29, 34, and 35.
was pivotal for accessing these crucially important intermediates.
In the case of furanosyl compounds, the five-membered ring
opened up in situ to afford directly the densely functionalized
pyrroles substituted with chiral functional groups, and the
pyranosyl compounds underwent ring opening with POCl3 in
DMF. A perusal of the structure of pyrroles in Table 2 also
suggests that a myriad of functional groups have been attached
to the ꢀ-position of pyrrole rings. Some of these groups, such
as chiral acyclic chains (27, 28, 29, 32, 33) or sugar residues
In conclusion, we have reported a straightforward and general
method for the synthesis of a wide range of polysubstituted
pyrroles from vinyl sulfone-modified carbohydrates. Our general
and regioselective approach to the synthesis of the vinyl sulfones
J. Org. Chem. Vol. 74, No. 2, 2009 671

Bhattacharya et al.
J ) 2.6 Hz); 5.90 (d, 1H, J ) 3.8 Hz); 6.27 (d, 1H, J ) 1.4 Hz);
6.57 (d, 1H, J ) 0.6 Hz); 7.26-7.37 (m, 7H); 7.77 (d, 2H, J ) 6.6
Hz). 13C NMR: δ 21.5, 26.2, 26.7, 72.6 (CH2), 76.9, 82.2, 83.2,
104.2, 111.9, 127.6 (CH2), 127.6, 127.8, 128.2, 128.3, 129.9, 135.9,
137.4, 144.8. HRMS (ES+), m/z calcd. for (M + H)+ C23H27O6S:
431.1528. Found: 431.1527.
(30, 31) would be very difficult, if not impossible, to introduce
at the ꢀ-position of a pyrrole ring with the currently available
methods. Wider applications of the new polysubstituted chiral
pyrroles are currently under study.
(2S,3S)-3,4-Dibenzyloxy-(1-C-p-tolylsulfonyl)butan-2-ol 18. To
a solution of 16 (1.2 g, 4.22 mmol) in DMF (15 mL) were added
thiocresol (2.62 g, 21.13 mmol) and TMG (1.46 g, 12.66 mmol).
The reaction mixture was heated for 5 h at 120-130 °C, cooled to
room temperature, and poured into satd. aq. NaCl solution (50 mL).
The mixture was extracted with EtOAc (3 × 30 mL). The EtOAc
layer was washed with satd. aq. NaHCO3 (2 × 25 mL), dried over
anhyd. Na2SO4, and evaporated under reduced pressure. The
resulting syrup was purified over silica gel to yield 17 (1.61 g,
93%). To a solution of 17 (1.6 g, 3.92 mmol) in methanol (30 mL)
was added MMPP (7.76 g, 15.68 mmol). The reaction mixture was
stirred for 6 h at room temperature and filtered. The filtrate was
evaporated under reduced pressure. The resulting residue was
neutralized with satd. aq. NaHCO3 (70 mL). The mixture was
extracted with EtOAc (3 × 30 mL). The organic layer was separated
and dried over anhyd. Na2SO4 and filtered, and the filtrate was
concentrated to dryness under reduced pressure to get the residue.
The crude residue was purified over silica gel to yield 18 (1.7 g,
quantitative). White solid. Mp: 126-129 °C. [R]D28: +34.5 ° (0.625,
THF). 1H NMR (CDCl3): δ 2.45 (s, 3H); 3.26-3.36 (m, 2H);
3.62-3.69 (m, 3H); 4.26-4.29 (m, 1H); 4.47-4.51 (m, 3H); 4.67
(d, 1H, J ) 12.0 Hz); 7.22-7.37 (m, 12H); 7.76 (d, 2H, J ) 8.0
Hz). 13C NMR: δ 21.6, 59.2 (CH2), 66.8, 69.0 (CH2), 72.6 (CH2),
73.5 (CH2), 78.0, 127.6, 127.8, 127.9, 128.0 (2 × C), 128.4 (2 ×
C), 129.8, 136.4, 137.6 (2 × C), 144.8. HRMS (ES+), m/z calcd.
for (M + H)+ C25H29O5S: 441.1736. Found: 441.1735.
1-{[(3R)-3,4-Dibenzyloxy-but-1-en-1-yl]sulfonyl}-4-methylben-
zene 11. To a solution of 18 (1.5 g, 3.40 mmol) in dry pyridine (25
mL) was added a solution of methanesulfonyl chloride (0.79 mL,
10.23 mmol) in dry pyridine (15 mL) at 0 °C. The mixture was
left overnight at 4 °C. The reaction mixture was poured into satd.
aq NaHCO3 (70 mL), and the aqueous phase was extracted with
dichloromethane (3 × 30 mL). Organic extracts were collected
together, dried over anhyd. Na2SO4, and filtered. The solvent was
evaporated under reduced pressure. The resulting residue was
purified over silica gel to yield 11 (1.33 g, 92%). White solid. Mp:
99-102 °C. [R]D28: -31.2 ° (0.625, CHCl3). 1H NMR (CDCl3): δ
2.43 (s, 3H); 3.53-3.62 (m, 2H); 4.25-4.28 (m, 1H); 4.51-4.61
(m, 4H); 6.63 (d, 1H, J ) 14.8 Hz); 6.94 (dd, 1H, J ) 4.4, 14.8
Hz); 7.24-7.35 (m, 12H); 7.74 (d, 2H, J ) 8.0 Hz). 13C NMR: δ
21.7, 71.5 (CH2), 72.1 (CH2), 73.5 (CH2), 76.4, 127.6, 127.7, 127.8
(2 × C), 128.0, 128.5 (2 × C), 130.0, 132.3, 137.2, 137.4, 137.7,
143.1, 144.5. HRMS (ES+), m/z calcd. for (M + H)+ C25H27O4S:
423.1630. Found: 423.1633.
Experimental Section
General Methods.10 3-O-Benzyl-5-deoxy-(5-C-p-tolylsulfide)-
1,2-O-isopropylidene-ꢀ-L-ido-1,4-furanose 14. To a well-stirred
solution of p-thiocresol (5.54 g, 44.69 mmol) and NaOMe (1.93 g,
35.75 mmol) in dry DMF (20 mL) was added a solution of
compound 13 (2.81 g, 4.46 mmol) in dry DMF (10 mL), and the
resulting solution was heated at 120-130 °C under N2 for a period
of 5 h. The reaction mixture was cooled to room temperature and
poured into a satd. aq. NaHCO3 soution (150 mL). The aqueous
phase was extracted with EtOAc (3 × 30 mL). Organic layers were
pooled together, dried over anhyd. Na2SO4, and evaporated under
reduced pressure. The crude mass was purified over silica gel. To
a solution of this compound in EtOH (10 mL) was added aq. HOAc
(75%, 25 mL). The reaction mixture was heated at 90 °C for 1.5 h
and cooled to room temperature. Volatile matters were evaporated
under reduced pressure to near dryness, and the residual acid was
coevaporated with toluene (3 × 10 mL) to get the crude mass. The
crude residue was purified over silica gel to yield 14 (1.1 g, 59%).
Colorless jelly. [R]D30: - 52.2 (c 1.14, CHCl3). 1H NMR
o
(CDCl3): δ 1.31 (s, 3H); 1.42 (s, 3H); 2.32 (s, 3H); 3.34-3.39 (m,
1H); 3.43-3.49 (m, 1H); 3.50-3.55 (m, 1H); 3.89 (d, 1H, J ) 3.2
Hz); 4.03-4.07 (m, 1H); 4.47 (d, 1H, J ) 11.6 Hz); 4.64-4.70
(m, 2H); 5.98 (d, 1H, J ) 3.6 Hz); 7.10 (d, 2H, J ) 8.0 Hz);
7.29-7.35 (m, 5H); 7.44 (d, 2H, J ) 8.0 Hz). 13C NMR: δ 21.2,
26.3, 26.7, 51.0, 60.5 (CH2), 71.8 (CH2), 78.9, 81.6, 81.8, 104.4,
111.7, 127.6, 128.0, 128.2, 128.6, 134.9, 136.9, 138.5. HRMS
(ES+), m/z calcd. for (M + Na)+ C23H28O5SNa: 439.1555. Found:
439.1556.
3-O-Benzyl-5-deoxy-(5-C-p-tolylsulfonyl)-1,2-O-isopropylidene-
ꢀ-L-ido-1,4-furanose 15. To a solution of 14 (0.84 g, 1.94 mmol)
in dry MeOH (20 mL) was added MMPP (3.85 g, 7.78 mmol),
and the reaction mixture was stirred at room temperature for 6 h
under N2. The reaction mixture was filtered through a celite bed,
and the filtrate was evaporated under reduced pressure. The crude
mass obtained was dissolved in EtOAc (30 mL), and the organic
layer was washed with satd. aq. solution of NaHCO3 (3 × 30 mL).
The organic layer was dried over anhyd. Na2SO4 and filtered, and
the filtrate was evaporated under reduced pressure to get a residue.
The crude residue was purified over silica gel to yield 15 (0.78 g,
o
86%). Colorless jelly. [R]D30: -31.5 (c 0.625, CHCl3). H NMR
(CDCl3): δ 1.28 (s, 3H); 1.42 (s, 3H); 2.42 (s, 3H); 3.53-3.62 (m,
1H); 3.95-4.04 (m, 3H; 4.36 (dd, 1H, J ) 3.0, 9.6 Hz); 4.46 (d,
1H, J ) 11.4 Hz); 4.54 (d, 1H, J ) 3.8 Hz); 4.64 (d, 1H, J ) 11.4
Hz); 5.76 (d, 1H, J ) 3.8 Hz); 7.26-7.39 (m, 7H); 7.84 (d, 2H, J
) 8.4 Hz). 13C NMR: δ 21.7, 26.3, 26.7, 58.5 (CH2), 66.9, 71.9
(CH2), 76.0, 80.8, 82.0, 104.7, 111.9, 128.0, 128.4, 128.7, 129.3,
129.4, 136.2, 136.6, 144.8. HRMS (ES+), m/z calcd. for (M + H)+
C23H29O7S: 449.1634. Found: 449.1635.
3,4-Isopropylidine-1,6-bis-p-tolylsulfonyl-D-mannitol 21. To a
well-stirred solution of the ditosylate 24 (4.00 g, 7.54 mmol) in
DMF (40 mL) was added p-thiocresol (9.34 g, 75.4 mmol) and
NaOMe (2.03 g, 37.70 mmol). The mixture was heated at 120-130
°C with stirring under N2. After 5 h, the reaction mixture was poured
into satd. aq. solution of NaHCO3, and the product was washed
with EtOAc (3 × 10 mL). The combined organic layer was dried
over anhyd. Na2SO4 and filtered through a short silica gel column
to afford the sulfide 20. To a solution of 20 (2.61 g, 6.01 mmol) in
dry MeOH (40 mL) was added MMPP (17.83 g, 36.06 mmol), and
the reaction mixture was stirred at room temperature for 6 h under
N2. The reaction mixture was then filtered through a celite bed,
and the filtrate was evaporated under reduced pressure. The crude
mass obtained was then dissolved in EtOAc (30 mL), and the
organic layer was washed with satd. aq. solution of NaHCO3 (3 ×
30 mL). Organic layers were collected and dried over anhyd.
Na2SO4 and filtered, and the filtrate was evaporated under reduced
3-O-Benzyl-5,6-didehydro-5,6-dideoxy-1,2-O-isopropylidene-(5-
C-p-tolylsulfonyl)-r-D-gluco-1,4-furanose 10. To a solution of 15
(0.54 g, 1.23 mmol) in dry pyridine (15 mL) was added a solution
of methanesulfonyl chloride (0.28 mL, 3.69 mmol) in dry pyridine
(5 mL) at 0 °C. The mixture was left overnight at 4 °C. The reaction
mixture was poured into satd. aq NaHCO3 (70 mL), and the aqueous
phase was extracted with dichloromethane (3 × 30 mL). Organic
extracts were collected together, dried over anhyd. Na2SO4, and
filtered. Et3N (5 mL) was added to the filtrate, and after stirring
for 15 min, the solvent was evaporated under reduced pressure.
The resulting residue was purified over silica gel to yield 10 (0.5
o
1
g, 98%). Colorless jelly. [R]D30: -8.7 (c 1.0, CHCl3). H NMR
(CDCl3): δ 1.28 (s, 3H); 1.39 (s, 3H); 2.42 (s, 3H); 4.15 (d, 1H, J
) 2.8 Hz); 4.49 (s, 2H); 4.57 (d, 1H, J ) 3.8 Hz); 4.79 (bd, 1H,
pressure to get a residue. The crude residue was purified over silica
28
gel to yield 21 (3.00 g, 80%). White solid. Mp: 116-117 °C. [R]D
:
672 J. Org. Chem. Vol. 74, No. 2, 2009

Densely Functionalized Chiral Pyrroles
o
1
o
1
+36.5 (0.625, CHCl3). H NMR (CDCl3): δ 1.17 (s, 6H); 2.44
(s, 6H); 3.15-3.28 (m, 2H); 3.52 (dd, 2H, J ) 1.6, 14.6 Hz);
3.74-3.78 (m, 2H); 3.95 (d, 2H, J ) 2.2 Hz); 4.07-4.16 (m, 2H);
7.35 (d, 4H, J ) 8.0 Hz); 7.80 (d, 4H, J ) 8.0 Hz). 13C NMR: δ
21.6, 26.7, 59.5 (CH2), 67.8 (CH2), 80.8, 110.3, 128.0, 129.9, 136.4,
145.0. HRMS (ES+), m/z calcd. for (M + H)+ C23H31O8S2:
499.1460. Found: 499.1468.
Colorless jelly. [R]D28: +39.8 (c 0.32, THF). H NMR (DMSO-
d6): δ 1.16-1.20 (m, 3H); 3.14-3.17 (m, 1H); 3.24-3.29 (m, 1H);
3.38 (s, 3H); 4.13-4.23 (m, 2H); 4.55-4.63 (m, 1H); 4.71-4.78
(m, 3H); 4.87-4.93 (m, 1H); 6.61 (s, 1H,); 7.22-7.39 (m, 20H);
11.83 (bs, 1H). 13C NMR: δ 14.7, 56.4, 60.1 (CH2), 66.1 (CH2),
69.8, 72.3 (CH2), 86.6, 98.9, 117.5, 119.1, 120.0, 123.6, 127.4,
127.5, 127.6, 128.3, 128.6, 139.8, 144.1, 160.8. HRMS (ES+), m/z
calcd. for (M + Na)+ C38H37NO6Na: 626.2519. Found: 626.2512.
Ethyl (4R,6S,7R)-7-(Benzyloxy)-6-methoxy-4-methyl-2,4,6,7-tet-
rahydropyrano[3,4-c]pyrrole-1-carboxylate 25. Following the gen-
(4R,5R)-2,2-Dimethyl-4,5-bis[(E)-2-(p-tolylsulfonyl)ethenyl]-1,3-
dioxolane 12. To a well-stirred solution of the sulfone 21 (2.00 g,
4.01 mmol) in pyridine (15 mL) was added a solution of
methanesulfonyl chloride (1.9 mL, 24.06 mmol) in pyridine (10
mL) dropwise at 0 °C under N2. The reaction mixture was kept
overnight at +4 °C. The reaction mixture was poured into a satd.
aq. solution of NaHCO3, and the product was extracted with EtOAc
(3 × 10 mL). The combined organic layer was dried over anhyd.
Na2SO4 and filtered, and the filtrate was concentrated under reduced
eral procedure, compound 4 (0.4 g, 1.03 mmol) was converted to
28
yield compound 25 (Yield: 0.32 g, 89%). Colorless jelly. [R]D
:
+39.8 ° (0.32, THF). 1H NMR (DMSO-d6): δ 1.20 (t, 3H, J ) 7.0
Hz); 1.35 (d, 3H, J ) 6.4 Hz); 3.39 (s, 3H); 4.11-4.26 (m, 2H);
4.62-4.84 (m, 4H); 4.92-4.97 (m, 1H); 6.79 (d, 1H, J ) 2.8 Hz);
7.21-7.29 (m, 5H); 11.82 (bs, 1H). 13C NMR: δ 14.7, 21.8, 56.0,
60.0 (CH2), 65.6, 70.6, 72.1 (CH2), 97.9, 117.3, 118.8, 122.8, 125.1,
127.4, 127.4, 128.3, 139.9. 160.8. HRMS (ES+), m/z calcd. for (M
+ Na)+ C19H23NO5Na: 368.1474. Found: 368.1479.
pressure to get a residue. The residue was purified over silica gel
28
to afford 12 (1.20 g, 65%). White solid. Mp: 177-179 °C. [R]D
:
o
1
+24.5 (0.625, CHCl3). H NMR (CDCl3): δ 1.39 (s, 6H); 2.42
(s, 6H); 4.31 (bs, 2H); 6.70 (d, 4H, J ) 14.8 Hz); 6.89 (d, 2H, J )
Ethyl (4S,6R,7S)-7-Benzyloxy-6-(benzyloxymethyl)-4-methoxy-
2,4,6,7-tetrahydropyrano[3,4-c]pyrrole-3-carboxylate 26. Following
the general procedure, compound 5 (0.2 g, 0.40 mmol) was
converted to yield compound 26 (Yield: 0.148 g, 81%). Colorless
15.2 Hz); 7.33 (d, 4H, J ) 8.0 Hz); 7.76 (d, 2H, J ) 8.0 Hz). 13
C
NMR: δ 21.5, 26.6, 78.3, 111.3, 127.8, 130.0, 133.2, 136.5, 138.6
144.8. HRMS (ES+), m/z calcd. for (M + H)+ C23H27O6S2:
463.1249. Found: 463.1248.
jelly. [R]D28: +34.2 (c 0.325, THF). 1H NMR (CDCl3): δ
o
General Procedure for the Synthesis of Pyrroles from Vinyl
Sulfone-Modified Carbohydrates. To a suspension of 90% tBuOK
(6 equiv) in dry THF (2 mL/mmol) at 0 °C was added ethyl
isocyanoacetate (5 equiv), and the resulting solution was stirred
for 15 min under N2. A solution of the appropriate vinyl sulfone-
modified carbohydrates (1 equiv) in dry THF (1 mL/mmol) was
added dropwise to the reaction mixture. The resulting solution was
heated under reflux with continuous stirring under N2 for 5 h. The
reaction mixture was cooled to room temperature, and the volatile
matters were evaporated under reduced pressure. The residue
obtained was triturated with EtOAc (30 mL). The organic layer
was washed with satd. aq. solution of NH4Cl (3 × 30 mL) and
separated. The organic layer was dried over anhyd. Na2SO4 and
filtered, and the filtrate was evaporated under reduced pressure to
get a crude mass. The crude residue was purified over silica gel to
get the pure product. Eluent:Pet.ether-EtOAc (3:1).
Ethyl (2R,4aR,6S,9bS)-6-Methoxy-2-phenyl-4a,6,8,9b-tetrahy-
dro-4H-[1,3]dioxino[4′,5′:5,6]pyrano[3,4-c]pyrrole-7-carboxylate 22.
Following the general procedure, compound 1 (0.15 g, 0.37 mmol)
was converted to yield compound 22 (Yield: 0.99 g, 76%). White
crystal. Mp: 117-119 °C. [R]D28: +15.2 o (c 0.625, THF). 1H NMR
(DMSO-d6): δ 1.27 (t, 3H, J ) 7.0 Hz); 3.42 (s, 3H); 3.85-3.95
(m, 2H); 4.15-4.26 (m, 3H); 4.69 (d, 1H, J ) 8.4 Hz); 5.62 (s,
1H); 5.80 (s, 1H); 6.89 (d, 1H, J ) 2.8 Hz); 7.36-7.47 (m, 5H);
11.99 (bs, 1H). 13C NMR: δ 14.7, 55.9, 60.2 (CH2), 64.6, 68.9
(CH2), 74.6, 96.6, 101.3, 118.0, 118.5, 119.8, 124.2, 126.8, 128.5,
129.3, 138.2. 160.3. HRMS (ES+), m/z calcd. for (M + Na)+
C19H21NO6Na: 382.1267. Found: 382.1269.
1.31-1.37 (m, 3H); 3.59 (s, 3H); 3.88 (d, 2H, J ) 10.0 Hz);
4.26-4.36 (m, 3H); 4.55-4.61 (m, 3H); 4.71-4.80 (m, 2H); 5.79
(s, 1H); 6.64 (d, 1H, J ) 2.0 Hz); 7.27-7.41 (m, 10H); 9.58 (bs,
1H). 13C NMR: δ 14.4, 55.8, 60.5 (CH2), 69.1 (CH2), 69.3, 69.9,
71.2 (CH2), 73.4 (CH2), 95.7, 117.9, 118.9, 121.9, 125.2, 127.6),
127.7 (2 × C), 127.8, 128.3, 128.4, 138.2, 138.4, 160.7. HRMS
(ES+), m/z calcd. for (M + Na)+ C26H29NO6Na: 474.1893. Found:
474.1893.
Ethyl 4-[(S)-1,4-Dioxaspiro[4.5]dec-2-yl(hydroxy)methyl]-3-
formyl-1H-pyrrole-2-carboxylate 27. Following the general pro-
cedure, compound 6 (0.16 g, 0.40 mmol) was converted to yield
28
compound 27 (Yield: 0.114 g, 82%). Colorless jelly. [R]D
:
+55.3 o (c 0.725, THF). 1H NMR (DMSO-d6): δ 1.24 (t, 3H, J )
7.0 Hz); 1.27-1.56 (m, 10H); 3.51 (d, 1H, J ) 9.6 Hz); 3.87-3.98
(m, 3H); 4.13-4.21 (m, 2H); 6.71 (s, 1H); 10.87 (s, 1H); 11.97
(bs, 1H). 13C NMR: δ 14.6, 23.9 (CH2), 24.1 (CH2), 25.1 (CH2),
34.9 (CH2), 36.5 (CH2), 60.1 (CH2), 65.9, 66.1 (CH2), 78.1 (CH2),
120.4, 109.4, 114.6, 122.1, 130.2, 132.1, 159.9, 188.9. HRMS
(ES+), m/z calcd. for (M + Na)+ C17H23NO6Na: 360.1423. Found:
360.1419.
Ethyl 4-[(1S)-2-(Benzyloxy)-1-hydroxyethyl]-3-formyl-1H-pyr-
role-2-carboxylate 28. Following the general procedure, compound
7 (0.10 g, 0.27 mmol) was converted to yield compound 28 (Yield:
0.74 g, 86%). Colorless jelly. [R]D28: +68.6 o (c 1.0, THF). 1H NMR
(DMSO-d6): δ 1.30 (t, 3H, J ) 7.0 Hz); 3.50-3.53 (m, 2H);
4.28-4.34 (m, 2H); 4.46-4.55 (m, 2H); 5.18-5.21 (m, 2H); 7.01
(d, 1H, J ) 2.0 Hz); 7.24-7.33 (m, 5H); 10.39 (s, 1H); 12.48 (bs,
1H). 13C NMR: δ 14.6, 61.3 (CH2), 66.2, 72.3 (CH2), 75.4 (CH2),
122.1, 124.3, 127.0, 127.6, 127.8, 128.5, 129.1, 139.1, 159.9, 188.8.
HRMS (ES+), m/z calcd. for (M + Na)+ C17H19NO5Na: 340.1161.
Found: 340.1166.
Ethyl (2R,4aR,6S,9bS)-6-Methoxy-2-phenyl-4a,6,8,9b-tetrahy-
dro-4H-[1,3]dioxino[4′,5′:5,6]pyrano[3,4-c]pyrrole-9-carboxylate 23.
Following the general procedure, compound 2 (0.2 g, 0.5 mmol)
was converted to yield compound 23. (Yield: 0.135 g, 78%). White
solid. Mp: 137-139 °C. [R]D28: +54.1 ° (c 0.625, THF). 1H NMR
(DMSO-d6): δ 1.02 (t, 3H, J ) 7.0 Hz); 3.38 (s, 3H); 3.79-3.85
(m, 1H); 3.92-3.98 (m, 1H); 4.06-4.12 (m, 2H); 4.23-4.27 (m,
1H); 4.81 (d, 1H, J ) 8.8 Hz); 5.05 (s, 1H); 5.82 (s, 1H); 6.94 (d,
1H, J ) 2.8 Hz); 7.34-7.37 (m, 3H); 7.46-7.47 (m, 2H); 11.94
(bs, 1H). 13C NMR: δ 14.4, 55.1, 60.1 (CH2), 64.9, 68.8 (CH2),
75.0, 96.0, 101.2, 118.0, 120.6 (2 × C), 122.8, 126.6, 128.3, 129.1,
Ethyl 3-[(1S)-2-(Benzyloxy)-1-hydroxyethyl]-4-formyl-1H-pyr-
role-2-carboxylate 29. Following the general procedure, compound
8 (0.15 g, 0.40 mmol) was converted to yield compound 29 (Yield:
o
1
0.116 g, 91%). Colorless jelly. [R]D28: +43.8 (c 0.82, THF). H
NMR (DMSO-d6): δ 1.26 (t, 3H, J ) 7.0 Hz); 3.46-3.61 (m, 2H);
4.25 (q, 2H, J ) 7.0 Hz); 4.47 (s, 2H); 5.57-5.65 (m, 2H);
7.18-7.34 (m, 5H); 7.73 (s, 1H); 9.96 (s, 1H); 12.53 (bs, 1H). 13
C
NMR: δ 14.6, 60.8 (CH2), 66.0, 72.3 (CH2), 75.3 (CH2), 120.4,
126.0, 127.5, 127.6, 128.5, 131.4, 133.3, 138.9, 160.8, 188.8 (CH).
HRMS (ES+), m/z calcd. for (M + Na)+ C17H19NO5Na: 340.1161.
Found: 340.1163.
Ethyl 3-[(3aR,5R,6S,6aR)-6-Methoxy-2,2-dimethyltetrahydro-
furo[2,3-d][1,3]dioxol-5-yl]-1H-pyrrole-2-carboxylate 30. Following
the general procedure, compound 9 (0.14 g, 0.32 mmol) was
138.5. 160.6. HRMS (ES+), m/z calcd. for (M
C19H21NO6Na: 382.1267. Found: 382.1259.
+
Na)+
Ethyl (4S,6S,7R)-7-(Benzyloxy)-6-methoxy-4-(triphenylmethy-
loxymethyl)-2,4,6,7-tetrahydropyrano[3,4-c]pyrrole-1-carboxy-
late 24. Following the general procedure, compound 3 (0.4 g, 1.03
mmol) was converted to yield compound 24 (Yield: 0.32 g, 90%).
J. Org. Chem. Vol. 74, No. 2, 2009 673

Bhattacharya et al.
converted to yield compound 30 (Yield: 0.91 g, 72%). Colorless
jelly. [R]D28: +34.5 o (c 0.625, THF). 1H NMR (DMSO-d6): δ 1.17
(t, 3H, J ) 7.0 Hz); 1.27 (s, 3H); 1.41 (s, 3H); 3.95 (d, 1H, J )
2.8 Hz); 4.07-4.15 (m, 3H); 4.33 (d, 1H, J ) 12.4 Hz); 4.70 (d,
1H, J ) 3.6 Hz); 5.61 (d, 1H, J ) 2.8 Hz); 5.99 (d, 1H, J ) 3.6
Hz); 6.28 (s, 1H); 6.94-6.96 (m, 3H); 7.19-7.21 (m, 3H); 11.74
(bs, 1H). 13C NMR: δ 14.5, 26.5, 26.9, 59.9 (CH2), 71.0 (CH2),
76.6, 82.0 (CH), 83.1, 104.3, 110.8, 111.1,117.9, 123.1, 126.5,
127.6,127.7, 128.4, 138.3. 160.7. HRMS (ES+), m/z calcd. for (M
+ Na)+ C21H25NO6Na: 410.1580. Found: 410.1578.
126.6, 160.8. HRMS (ES+), m/z calcd. for (M Na)+
+
C19H24N2O6Na: 399.1532. Found: 399.1530.
Ethyl 3-Formyl-4-[(2R,4S,5R)-5-hydroxy-2-phenyl-1,3-dioxan-
4-yl]-1H-pyrrole-2-carboxylate 34. To an ice cold solution of POCl3
(0.02 mL, 0.21 mmol) in dry DMF (2 mL) was added a solution of
compound 32 (0.051 g, 0.14 mmol) in dry DMF (2 mL). The
reaction mixture was allowed to warm up to room temperature,
and the reaction was continued for 1.5 h under stirring at N2. The
reaction mixture was poured slowly into cold satd. aq. NaHCO3
solution (30 mL). The mixture was extracted with EtOAc (3 × 15
mL) and separated. The EtOAc layer was dried over anhyd. Na2SO4
and filtered, and the filtrate was evaporated under reduced pressure.
The resulting syrup was purified over silica gel to yield 34 (0.034
g, 73%). Colorless jelly. [R]D28: + 61.6 o (c 0.375, THF). 1H NMR
(DMSO-d6): δ 1.17 (t, 3H, J ) 7.0 Hz); 3.58-3.64 (m, 1H);
3.85-3.88 (m, 1H); 4.17-4.20 (m, 1H); 4.21-4.29 (m, 2H); 5.10
(d, 1H, J ) 5.6 Hz); 5.52 (d, 1H, J ) 9.2 Hz); 5.63 (s, 1H);
7.33-7.43 (m, 5H); 7.62 (d, 1H, J ) 3.2 Hz); 10.12 (s, 1H); 12.53
(bs, 1H). 13C NMR: δ 14.6, 60.7 (CH2), 66.7, 72.1 (CH2), 77.4,
101.4, 122.4, 125.5, 126.7, 128.2, 128.5, 129.0, 129.2, 138.6, 160.7,
187.0. HRMS (ES+), m/z calcd. for (M + Na)+ C18H19NO6Na:
368.1110. Found: 368.1119.
Ethyl 4-[(3aR,5R,6S,6aR)-6-Methoxy-2,2-dimethyltetrahydro-
furo[2,3-d][1,3]dioxol-5-yl]-1H-pyrrole-2-carboxylate 31. Following
the general procedure, compound 10 (0.248 g, 0.57 mmol) was
converted to yield compound 31 (Yield: 0.18 g, 81%). White crystal.
o
1
Mp: 87-89 °C (decomposed). [R]D28: +39.3 (c 1.0, THF). H
NMR (DMSO-d6): δ 1.23-1.26 (m, 6H); 1.43 (s, 3H); 3.81 (d,
1H, J ) 2.4 Hz); 4.17-4.28 (m, 3H); 4.49 (d, 1H, J ) 12.0 Hz);
4.75 (d, 1H, J ) 3.6 Hz); 5.05 (d, 1H, J ) 2.4 Hz); 5.90 (d, 1H,
J ) 3.6 Hz); 6.84 (s, 1H); 7.02 (s,1H); 7.13-7.15 (m, 2H);
7.25-7.27 (m, 3H); 11.78 (bs, 1H). 13C NMR: δ 14.7 (CH3), 55.9
(CH3), 60.2 (CH2), 64.6 (CH), 68.9 (CH2), 74.6 (CH), 96.6 (CH),
101.3 (CH), 118.0 (CH), 118.5 (C), 119.8 (C), 124.2 (C), 126.8
(CH), 128.5 (CH), 129.3 (CH), 138.2 (C). 160.3 (C). HRMS (ES+),
m/z calcd. for (M + Na)+ C21H25NO6Na: 410.1580. Found:
410.1572.
Ethyl 4-Formyl-3-[(2R,4S,5R)-5-hydroxy-2-phenyl-1,3-dioxan-
4-yl]-1H-pyrrole-2-carboxylate 35. Compound 33 (0.051 g, 0.14
mmol) was converted to 35 (0.035 g, 73%, colorless jelly) following
the procedure described for the synthesis of 34. [R]D28: +59.3 o (c
Ethyl 3-[(1R)-1,2-Dimethoxyethyl]-1H-pyrrole-2-carboxylate 32.
Following the general procedure, compound 11 (0.53 g, 1.25 mmol)
was converted to yield compound 32 (Yield: 0.395 g, 83%). White
solid. Mp: 144-145 °C. [R]D28: +18.7 o (c 0.725, THF). 1H NMR
(CDCl3): δ 1.27 (t, 3H, J ) 7.0 Hz); 3.63-3.66 (m, 1H); 3.73-3.78
(m, 1H); 4.26 (q, 2H, J ) 7.2 Hz); 4.47 (d, 1H, J ) 12.0 Hz);
4.60-4.65 (m, 3H); 5.37-5.40 (m, 1H); 6.43-6.44 (m, 1H);
6.91-6.92 (m, 1H); 7.29-7.37 (m, 10H); 9.03 (bs, 1H). 13C NMR:
δ 14.4, 60.4 (CH2), 70.8 (CH2), 73.0 (CH2), 73.8, 74.4 (CH2), 109.8,
111.1,119.5, 122.7, 127.4 (2 × C), 127.6,127.8, 128.1, 128.3 (2 ×
C), 129.7, 138.7, 138.9, 160.4. HRMS (ES+), m/z calcd. for (M +
Na)+ C23H25NO4Na: 402.1681. Found: 402.1672.
Diethyl 3,3′-[(4R,5R)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl]bis(1H-
pyrrole-2-carboxylate) 33. Following the general procedure, com-
pound 12 (0.1 g, 0.21 mmol) was converted to yield compound 33
(Yield: 0.75 g, 92%). Colorless jelly. [R]D28: +31.5 o (c 0.625, THF).
1H NMR (DMSO-d6): δ 1.17 (t, 6H, J ) 7.0 Hz); 1.45 (s, 6H);
3.96-4.05 (m, 2H); 4.07-4.15 (m, 2H); 5.51 (s, 2H); 6.31 (d, 2H,
J ) 2.4 Hz); 6.91 (d, 2H, J ) 2.4 Hz); 11.74 (bs, 2H). 13C NMR:
δ 14.6, 27.7, 26.9, 59.8 (CH2), 76.3, 107.7, 109.5, 120.1, 123.3,
1
0.62, THF). H NMR (DMSO-d6): δ 1.17 (t, 3H, J ) 7.0 Hz);
3.57-3.62 (m, 1H); 3.78-3.84 (m, 1H); 4.14-4.18 (m, 1H);
4.30-4.35 (m, 2H); 5.05-5.11 (m, 2H); 5.59 (s, 1H); 7.21 (s, 1H);
7.30-7.38 (m, 5H); 10.46 (s, 1H); 12.58 (bs, 1H). 13C NMR: δ
14.6, 61.3 (CH2), 65.2, 71.8 (CH2), 76.5, 100.8, 123.3, 124.0, 126.1,
126.5, 127.0, 128.3, 128.9, 138.6, 160.0, 188.5. HRMS (ES+), m/z
calcd. for (M + Na)+ C18H19NO6Na: 368.1110. Found: 368.1115.
Acknowledgment. TP thanks the Department of Science and
Technology (DST), New Delhi, for financial support. RB, AKA,
and DD thank CSIR, New Delhi for a fellowship. DST is also
thanked for the creation of 400 MHz facility under IRPHA
program and DST-FIST for single crystal X-ray facility.
Supporting Information Available: Experimental proce-
dures, full spectroscopic data of selected compounds,and CIF
files of 22. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO801948M
674 J. Org. Chem. Vol. 74, No. 2, 2009