Synthesis of cyclopentane building blocks via an intramolecular C-H insertion reaction of a chiral pool derived α-diazo-γ-hydroxy-β-ketosulfone

Article abstract of DOI:10.1016/S0040-4039(03)01619-8

A highly functionalized cyclopentanone building block 13 was prepared by a facile Rh-catalyzed intramolecular C-H insertion reaction of an enantiopure α-diazo-γ-hydroxy-β-ketosulfone 12, in turn derived from an α-hydroxy acid 2. A cyclic γ-hydroxy vinyl s

Full text of DOI:10.1016/S0040-4039(03)01619-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6405–6408
Synthesis of cyclopentane building blocks via an intramolecular
CꢀH insertion reaction of a chiral pool derived
a-diazo-g-hydroxy-b-ketosulfone
Saumitra Sengupta* and Somnath Mondal
Department of Chemistry, Jadavpur University, Kolkata 700 032, India
Received 2 May 2003; revised 17 June 2003; accepted 27 June 2003
Abstract—A highly functionalized cyclopentanone building block 13 was prepared by a facile Rh-catalyzed intramolecular CꢀH
insertion reaction of an enantiopure a-diazo-g-hydroxy-b-ketosulfone 12, in turn derived from an a-hydroxy acid 2. A cyclic
g-hydroxy vinyl sulfone 16 was also prepared from 13.
© 2003 Elsevier Ltd. All rights reserved.
In a program directed towards the synthesis of
triquinane skeletons,1 we identified the cyclopentanone
derivative 1 as a key building block. By virtue of its
dense functionalization and an embedded gem-dimethyl
substitution, 1 promised to serve as a common interme-
diate for the synthesis of various sesquiterpenes and
related natural products. However, its contiguous sub-
stitution pattern including the presence of chiral cen-
ters, made its synthesis a vastly challenging task. Not
surprisingly, several attempts at its synthesis via classi-
cal Dieckmann-type cyclization reactions failed.2 Still in
pursuit, our attention was drawn to the large number of
reports on five-membered ring construction via cata-
lyzed intramolecular CꢀH insertion reactions of a-dia-
zocarbonyl compounds.3 Among the catalysts used for
these reactions, Rh-salts are the overwhelming favor-
ites, although examples of Cu-catalyzed intramolecular
CꢀH insertion reactions leading to five-membered rings
are also known.4 Both carbocyclic and heterocyclic
five-membered rings have been synthesized in this way.3
Non-racemic syntheses of these ring systems are also
known either via the use of chirally modified Rh-cata-
lysts or by using enantiopure diazocarbonyl substrates.
There are several reports on the synthesis of cyclopen-
tane derivatives using this regime, although examples of
the non-racemic variety are less documented.3c,5
Intramolecular CꢀH insertion reactions, in view of their
mild and neutral reaction conditions and high func-
tional group tolerance, appeared to be an attractive
strategy for the synthesis of a highly functionalized
cyclopentanone derivative such as 1. Our success
towards this end is described in this letter.
The O-acetyl a-diazo-b-ketosulfone 6 was initially cho-
sen as the substrate for the CꢀH insertion reaction
towards 1. The choice of the isobutyl side chain in 6
was of critical importance. Taber et al. have shown that
for a series of a-diazoketones, intramolecular CꢀH
insertion reactions usually occur at the g-carbon to
produce five-membered rings and that they occur pref-
erentially at the g-carbon which is more substituted (2°
> 1°).6 Accordingly, in 6, we chose an isobutyl side
chain since it would provide a highly favorable methine
carbon (2°) as the insertion terminus leading to facile
five-membered ring construction and, in the process,
would also set up the gem-dimethyl substitution pattern
in 1. The synthesis of 6 is shown in Scheme 1. Starting
from the a-hydroxy acid 2 (readily prepared from L-
leucine)7 which via its acetate 3,8 and the corresponding
diazoketone 4 (77%), was converted in two easy steps to
Keywords: cyclopentanone; a-diazo-b-ketosulfone; CꢀH insertion
reaction; Rh2(OAc)4; a-hydroxy acid.
* Corresponding author. Fax: 91 33 24146266; e-mail: jusaumitra@
yahoo.co.uk
the g-acetoxy-b-ketosulfone
5 in a good overall
yield.9,10 Diazo-transfer on 5 with TsN3 (Et3N, CH2Cl2,
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01619-8

6406
S. Sengupta, S. Mondal / Tetrahedron Letters 44 (2003) 6405–6408
Scheme 1. Reagents and conditions: (i) CH3COCl, rt; (ii) SOCl2, benzene, reflux then excess CH2N2, ether, 0°C; (iii) 48% HBr,
ether, 0°C; (iv) NaSO2Tol, DMF, rt; (v) TsN3, Et3N, CH2Cl2, rt; (vi) 1% Rh2(OAc)4.
rt)11 then gave 6 in moderate yield. However, repeated
attempts at the Rh2(OAc)4 catalyzed intramolecular
CꢀH insertion reaction in 6 failed to provide the desired
cyclopentanone 7 under a variety of conditions. The use
of Cu-catalysts, e.g. Cu(acac)2 or Cu2O also resulted in
failures. In all these attempts, although the substrate
was fully consumed, no isolable products could be
identified by TLC analysis of the reaction mixture. We
attributed these failures to the presence of the neighbor-
ing acetate functionality in 6 which probably engaged
the incipient carbenoid into intramolecular ylide forma-
tion (leading to 8), thereby suppressing the CꢀH inser-
tion pathway. That ylide formation can effectively
compete with CꢀH insertion reactions in Rh-catalyzed
reactions of suitably disposed a-diazoketones has been
reported by others.12
a-diazo-b-ketosulfone 12 is shown in Scheme 2. Thus,
the a-hydroxy methyl ester 913 was first protected as the
TBS ether to give 10 (80%) and the latter reacted with
a,a-dilithio methyl tolyl sulfone (CH3SO2Tol, 2 equiv.
n-BuLi, THF, 0°C)14 to give the OTBS substituted
b-ketosulfone 11 in good yield. Diazo-transfer reaction
onto 11, as before with TsN3,11 then produced the key
a-diazo-b-ketosulfone 12 in 85% yield. Most gratify-
ingly, exposure of 12 to 1% Rh2(OAc)4 (CH2Cl2, rt,
slow addition of the substrate) smoothly gave rise to
the desired cyclopentanone derivative 13 (77%) as a
mixture of diastereomers (80/20 by NMR). That the
CꢀH insertion reaction had taken place at the side
chain methine carbon in 12, i.e. its isopropyl group had
been transformed into a gem-dimethyl substituent in
1
13, was clearly evident from the H NMR analysis of
these two compounds. Thus, the signal for the methine
proton of 12 (l 1.52–1.70, m) was absent in 13. More-
over, the pair of three proton doublets at l 0.83 and
0.85 in 12 due to its two terminal methyl groups were
replaced by a pair of three proton singlets (at l 0.80
and 0.83 in the major diastereomer) in 13 due to the
gem-dimethyl substitution pattern.
The acetate protecting group was hence discarded and
the non-interfering OTBS group chosen instead. Others
have shown that in intramolecular CꢀH insertion reac-
tions of d-hydroxy-a-diazo-b-keto esters, an OTBS pro-
tecting group effectively blocks competing oxonium
ylide formation.5f The synthesis of the OTBS protected
Scheme 2. Reagents and conditions: (i) TBS-Cl, cat. imidazole, Et3N, CH2Cl2, rt; (ii) CH3SO2Tol, 2 equiv. n-BuLi, THF, −78 to
0°C; (iii) TsN3, Et3N, CH2Cl2, rt; (iv) 1% Rh2(OAc)4, CH2Cl2, rt.

S. Sengupta, S. Mondal / Tetrahedron Letters 44 (2003) 6405–6408
6407
Scheme 3. Reagents and conditions: (i) NaBH4, MeOH–THF, 0°C; (ii) MsCl, py, rt.
References
In the course of this investigation, we also examined the
Rh-catalyzed reaction of the diazoketone 14 which
lacks the sulfone group present in 12. However, only
dimerization and decomposition products were
obtained in this case. Thus, appropriate pairing of the
reaction centers, i.e. a methine insertion terminus and a
highly electrophilic carbenoid carbon, appears to be
essential for the CꢀH insertion reaction to take place
successfully.
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With 13 in hand, we briefly examined some of its
chemistry (Scheme 3). Reductive desulfonation to the
a-hydroxy ketone 15 was first attempted since the latter
appeared to be an ideal precursor to a number of novel
C2-symmetric cyclic diols. However, treatment of 13
with Na(Hg) or Al(Hg) invariably led to decomposition
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In summary, we have described a facile synthetic entry
into highly functionalized cyclopentane derivatives via
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Acknowledgements
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S.M. thanks Jadavpur University for a research fellow-
ship under the UGC-JRF scheme.

6408
S. Sengupta, S. Mondal / Tetrahedron Letters 44 (2003) 6405–6408
10. Representative physical data for selected compounds. 4:
yellow oil; [h]2D0 −56.1 (c 5.5, CHCl3); IR (neat) 2100,
C20H32N2O4SSi: C, 56.60; H, 7.54; N, 6.60. Found: C,
56.68; H, 7.50; N, 6.08%. 13: colorless oil; IR (CHCl3)
1
1735, 1635, 1350 cm−1
;
1H NMR (200 MHz, CDCl3) l
3000, 1750, 1590, 1460, 1190 cm−1; H NMR (300 MHz,
0.90–1.00 (m, 6H), 1.50–1.80 (m, 3H), 2.12 (s, 3H), 5.08
(dd, 1H, J=4.0, 8.0 Hz), 5.39 (s, 1H). Anal. calcd for
C9H14N2O3: C, 54.54; H, 7.04; N, 14.14. Found: C, 54.18;
H, 7.03; N, 13.83%. 5: colorless oil; [h]2D0 −23.9 (c 4.2,
CDCl3, major diastereomer) l 0.00 (s, 3H), 0.01 (s, 3H),
0.77 (s, 9H), 0.80 (s, 3H), 0.83 (s, 3H), 2.16 (dd, 1H,
J=8.5, 12.5 Hz), 2.28–2.38 (m, 1H), 2.36 (s, 3H), 3.47 (br
s, 1H), 4.24 (dd, 1H, J=8.5, 3.0 Hz), 7.22–7.26 (m, 2H),
7.71 (d, 2H, J=8.0 Hz). Anal. calcd for C20H32O4SSi: C,
60.60; H, 8.08. Found: C, 60.83; H, 7.78%.
1
CHCl3); IR (neat) 1720, 1595, 1450 cm−1; H NMR (100
MHz, CDCl3) l 0.92–1.00 (m, 6H), 1.56–1.80 (m, 3H),
2.14 (s, 3H), 2.46 (s, 3H), 4.12–4.48 (m, 2H), 5.18 (dd,
1H, J=5.0, 8.0 Hz), 7.40 (d, 2H, J=8.0 Hz), 7.86 (d, 2H,
J=8.0 Hz). Anal. calcd for C16H22O5S: C, 58.89; H, 6.74.
Found: C, 58.50; H, 6.94%. 6: yellow oil; [h]2D0 +38.8 (c
11. Regitz, M.; Hocker, J.; Liedhegener, A. Org. Synth. 1973,
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0.4, CHCl3); IR (neat) 2100, 1745, 1665, 1595, 1365 cm−1
;
1H NMR (300 MHz, CDCl3) l 0.95 (d, 6H, J=6.6 Hz),
1.60–1.80 (m, 3H), 2.06 (s, 3H), 2.45 (s, 3H), 5.36 (dd,
1H, J=4.0, 9.6 Hz), 7.37 (d, 2H, J=8.3 Hz), 7.89 (d, 2H,
J=8.3 Hz). Anal. calcd for C16H20N2O5S: C, 54.54; H,
5.68; N, 7.95. Found: C, 54.62; H, 5.65; N, 7.91%. 11:
colorless oil: [h]2D7 −8.0 (c 1.4, CHCl3); IR (neat) 2950,
13. Prepared from 2 via an Ni-catalyzed esterification reac-
tion: Ram, R. N.; Charles, I. Tetrahedron 1997, 53, 7335.
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1
2850, 1720, 1590, 1460, 1320 cm−1; H NMR (300 MHz,
CDCl3) l 0.01 (s, 3H), 0.05 (s, 3H), 0.85 (d, 3H, J=3.0
Hz), 0.87 (d, 3H, J=3.0 Hz), 0.89 (s, 9H), 1.30–1.45 (m,
2H), 1.45–1.65 (m, 1H), 2.44 (s, 3H), 4.11 (dd, 1H,
J=6.2, 7.3 Hz), 4.22 (d, 1H, J=15.3 Hz), 4.47 (d, 1H,
J=15.3 Hz), 7.36 (d, 2H, J=8.4 Hz), 7.81 (d, 2H, J=8.4
Hz). Anal. calcd for C20H34O4SSi: C, 60.30; H, 8.54.
Found: C, 60.22; H, 8.60%. 12: yellow oil; [h]2D0 −5.9 (c
3.8, CHCl3); IR (neat) 2920, 2840, 2100, 1710, 1590,
1450, 1340 cm−1; 1H NMR (300 MHz, CDCl3) l −0.09 (s,
3H), 0.00 (s, 3H), 0.83 (s, 9H), 0.85 (d, 3H, J=6.0 Hz),
0.88 (d, 3H, J=6.0 Hz), 1.20–1.50 (m, 2H), 1.52–1.70 (m,
1H), 2.44 (s, 3H), 4.16 (dd, 1H, J=6.0, 8.0 Hz), 7.33 (d,
2H, J=8.1 Hz), 7.91 (d, 2H, J=8.1 Hz). Anal. calcd for