Asymmetric synthesis of 2-alkyl-4-hydroxycyclohex-2-en-1-ones by scandium(III) triflate-catalyzed fragmentation of 2-alkyl-3-iodo-1-oxocyclohexan-2,4-carbolactones

Article abstract of DOI:10.1016/j.tetlet.2009.02.016

Fragmentation of (2S,3S,4S)-2-allyl-3-iodo-1-oxocyclohexan-2,4-carbolactone to (4S)-2-allyl-4-hydroxycyclohex-2-en-1-one, a chiral building block of (-)-platensimycin, proceeded efficiently by using scandium(III) triflate in DMF-H₂O (1:3) at 10

Full text of DOI:10.1016/j.tetlet.2009.02.016

Tetrahedron Letters 50 (2009) 1917–1919
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Tetrahedron Letters
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Asymmetric synthesis of 2-alkyl-4-hydroxycyclohex-2-en-1-ones
by scandium(III) triflate-catalyzed fragmentation of 2-alkyl-3-iodo-1-
oxocyclohexan-2,4-carbolactones
*
Jun-ichi Matsuo , Mizuki Kawano, Kosuke Takeuchi, Hiroyuki Tanaka, Hiroyuki Ishibashi
School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Fragmentation of (2S,3S,4S)-2-allyl-3-iodo-1-oxocyclohexan-2,4-carbolactone to (4S)-2-allyl-4-hydroxy-
cyclohex-2-en-1-one, a chiral building block of (ꢀ)-platensimycin, proceeded efficiently by using scan-
dium(III) triflate in DMF–H2O (1:3) at 100 °C.
Received 25 December 2008
Revised 30 January 2009
Accepted 5 February 2009
Available online 8 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Fragmentation
Acid catalysis
Chiral building block
We have recently reported1 a stereocontrolled formal synthesis
of ( )-platensimycin (1):2 a racemic caged compound 5, Nicolaou’s
intermediate for the total synthesis of 1,3 was synthesized by using
stereoselective Diels–Alder reaction between enone 2 and siloxydi-
ene 3 to compound 4 as a key step (Scheme 1). Since all the stereo-
centers in 5 were controlled by the stereochemistry presented in 2,
the preparation of enantiomerically pure (S)-2 is required for the
asymmetric synthesis of (ꢀ)-1. Optically pure 2-alkyl-4-hydroxy-
cyclohex-2-en-1-ones are important chiral building blocks in or-
ganic synthesis,4 and a method for their efficient preparation
needs to be developed.
Schultz et al. reported that LiOH-mediated hydrolysis of iodo-
lactone 9, which was prepared from chiral amide 8 by Birch reduc-
tion, alkylation,5 hydrolysis, and iodolactonization, gave 6 as the
major product only when R was the methyl group (6:7 = 71:12,
Scheme 2, path a).6 Butenolide 7 was generally obtained as the ma-
jor product when R was a substituent larger than the methyl group
(path b). Therefore, it was expected that 2-allyl-4-hydroxycycloh-
exenone (6, R = allyl) would not be obtained efficiently by the basic
hydrolysis of 9, and it was thought that acid-catalyzed fragmenta-
tion of 9 might change the reaction course7 and that 6 would be
prepared effectively even when the substituent at the 2-position
(R) was larger than the methyl group. Based on this idea, we found
appropriate reaction conditions for the planned acid-catalyzed
fragmentation of 9–6, and we report here the results obtained in
this research.
In order to synthesize optically pure (S)-2, which is a chiral
building block for the synthesis of (ꢀ)-1, we employed chiral
amide ent-8 (Scheme 3). According to Schulz’s procedure,6 Birch
reduction of ent-8 followed by alkylation with 1-bromo-3-(phenyl-
thio)propane gave 10 in 78% yield. Hydrolysis of the enol ether
moiety with diluted hydrochloric acid, oxidation of the phenylthio
group with mCPBA, and iodolactonization of the formed sulfoxide
proceeded readily to afford iodolactone 11. Elimination of the
phenylsulfinyl group in refluxing xylene gave 12 in 76% yield,
and the optical purity of 12 at this point was determined to be
89% ee by chiral HPLC. This result suggests that the diastereoselec-
tivity for alkylation to 10 is 89% de. Optically pure 12 (>99% ee)8
was obtained by recrystallization of 12 with cyclohexane.
As suggested in Schultz’s report,6 basic hydrolysis of 12 with
LiOH in THF–H2O (1:2) gave the desired product (S)-13 only in
5% yield, and undesired butenolide carboxylic acid (R)-14 was ob-
tained as the major product (74% yield, Eq. 1):
ð1Þ
Acid-catalyzed hydrolysis of 12 was then investigated by
employing various Brønsted acids and Lewis acids in DMF–H2O
(1:3)9 at 100 °C (Table 1). All the Brønsted acids and Lewis acids
employed afforded the desired compound 13 as the major product.
* Corresponding author. Tel./fax: +81 76 234 4439.
E-mail address: jimatsuo@p.kanazawa-u.ac.jp (J. Matsuo).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.016

1918
J. Matsuo et al. / Tetrahedron Letters 50 (2009) 1917–1919
Scheme 1. Formal synthesis of ( )-platensimycin (1).
Scheme 2. Schultz and Khim’s report on hydrolysis of 9 under basic conditions.6b
Table 1
Acid-catalyzed fragmentation of 12 to (S)-13a
Entry
Acid cat.
13 (% yieldb)
14 (% yieldb)
1c
2
3
4
5
6
H2SO4
TsOH
TfOH
Sc(OTf)3
La(OTf)3
Yb(OTf)3
18
16
13
77
18
40
0
0
0
10
6
2
a
One equivalent of acid catalysis was employed in DMF–H2O (55
Isolated yield.
Sulfuric acid (0.5 equiv) was employed.
lM).
b
c
Scheme 3. Preparation of optically pure 12.
Table 2
Sc(OTf)3-catalyzed fragmentation of 9–6a
10
It was found that Sc(OTf)3 catalyzed the desired fragmentation
most efficiently to afford (S)-13 in 77% yield, and it was confirmed
by chiral HPLC analysis that racemization did not take place in this
step, and optically pure (S)-13 (>99% ee) was formed (entry 4).11
The fragmentation proceeded very slowly under catalysis with
Brønsted acids such as sulfuric acid, TsOH, and TfOH, and most of
starting materials were recovered in these cases (entries 1–3). Acti-
vation with Ln(OTf)3 and Yb(OTf)3 was also insufficient for smooth
fragmentation of 12 to 13 (entries 5 and 6).
The scope and limitations of the present Sc(OTf)3-catalyzed
fragmentation of iodolactones 9 to 2-alkyl-4-hydroxycyclohex-2-
en-1-ones 6 were examined (Table 2). The fragmentation of iodo-
lactones 9a–c having n-butyl, 3-phenylpropyl, and 3-(benzyl-
Entry
R
9
Time (h)
6 (% yieldb)
7 (% yieldb)
1
2
3
4
Bu
9a
9b
9c
9d
23
23
21
18
6a (62)
6b (53)
6c (71)
6d (17)
7a (13)
7b (7)
7c (trace)
7d (56)
Ph(CH2)3
BnO(CH2)3
PhCH2
a
One equivalent of Sc(OTf)3 was employed in DMF–H2O (55
Isolated yield.
lM).
b
oxy)propyl groups as
R
gave the corresponding 4-
hydroxycyclohexenones 6a–c as the major products, whereas frag-
mentation of iodolactone 9d bearing a benzyl group as R gave but-
enolide 7d as the major product. These results suggest that the
present Sc(OTf)3-catalyzed fragmentation of 9–6 proceeds
smoothly when relatively linear groups are substituted as R at
the 2-position of 9.
A proposed mechanism for Sc(OTf)3-catalyzed fragmentation of
9–6 is shown in Scheme 4. Scandium triflate activates ester car-
bonyl group of 9, and the -butyrolactone moiety is hydrolyzed
to give hydroxy carboxylic acid 15. Decarboxylation proceeds via
c

J. Matsuo et al. / Tetrahedron Letters 50 (2009) 1917–1919
1919
3. (a) Nicolaou, K. C.; Li, A.; Edmonds, D. J. Angew. Chem., Int. Ed. 2006, 45, 7086–
7090; (b) Nicolaou, K. C.; Edmonds, D. J.; Li, A.; Tria, G. S. Angew. Chem., Int. Ed.
2007, 46, 3942–3945; (c) Li, P.; Payette, J. N.; Yamamoto, H. J. Am. Chem. Soc.
2007, 129, 9534–9535; (d) Lalic, G.; Corey, E. J. Org. Lett. 2007, 9, 4921–4923;
(e) Nicolaou, K. C.; Pappo, D.; Tsang, K. Y.; Gibe, R.; Chen, D. Y. K. Angew. Chem.,
Int. Ed. 2008, 47, 944–946; (f) Kim, C. H.; Jang, K. P.; Choi, S. Y.; Chung, Y. K.; Lee,
E. Angew. Chem., Int. Ed. 2008, 47, 4009–4011; (g) Zou, Y.; Chen, C.-H.; Taylor, C.
D.; Foxman, B. M.; Snider, B. B. Org. Lett. 2007, 9, 1825–1828; (h) Nicolaou, K. C.;
Tang, Y.; Wang, J. Chem. Commun. 2007, 1922–1923; (i) Tiefenbacher, K.;
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Mulzer, J. Angew. Chem., Int. Ed. 2008, 47, 2548–2555.
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A. S.; Findik, H.; Kose, E. Tetrahedron: Asymmetry 2004, 15, 777–781; (c)
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Lett. 2007, 17, 553–557; (d) Barfoot, C. W.; Burns, A. R.; Edwards, M. G.;
Kenworthy, M. N.; Ahmed, M.; Shanahan, S. E.; Taylor, R. J. K. Org. Lett. 2008, 10,
353–356; (e) Arthurs, C. L.; Lingley, K. F.; Piacenti, M.; Stratford, I. J.; Tatic, T.;
Whitehead, R. C.; Wind, N. S. Tetrahedron Lett. 2008, 49, 2410–2413.
5. Schultz, A. G.; Macielag, M.; Sundararaman, P.; Taveras, A. G.; Welch, M. J. Am.
Chem. Soc. 1988, 110, 7828–7841.
6. (a) Schultz, A. G.; Dai, M.; Khim, S.-K.; Pettus, L.; Thakkar, K. Tetrahedron Lett
1998, 39, 4203–4206; (b) Khim, S.-K.; Dai, M.; Zhang, X.; Chen, L.; Pettus, L.;
Thakkar, K.; Schultz, A. G. J. Org. Chem. 2004, 69, 7728–7733; (c) Dai, M.; Zhang,
X.; Khim, S.-K.; Schultz, A. G. J. Org. Chem. 2005, 70, 384–387.
Scheme 4. Proposed mechanism for Sc(OTf)3-catalyzed fragmentation of 9 to 6.
a conformer 150 in a concerted pathway to form iodo ketone 16,
and successive elimination of HI takes place to give 6.
In summary, we established an efficient method for the prepa-
ration of (4S)-2-allyl-4-hydroxycyclohex-2-en-1-one ((S)-13) by
Sc(OTf)3-catalyzed fragmentation of iodolactone 12 in DMF-H2O
at 100 °C. Asymmetric synthesis of platensimycin (1) can be per-
formed by employing thus-obtained (S)-13. The Sc(OTf)3-catalyzed
fragmentation is also useful for the preparation of other optically
pure 2-alkyl-4-hydroxycyclohex-2-en-1-ones 6 from iodolactones
9, which are readily prepared from chiral amide 8.
7. House, H. O. In Modern Synthetic Reactions; Benjamin: California, 1972. Chapter
9.
8. (2S,3S,4S)-2-Allyl-3-iodo-1-oxocyclohexan-2,4-carbolactone (12): mp 113.0–
114.0 °C (cyclohexane); ½ ꢁ
a 2D6 +186.2 (c 0.744, CHCl3); 1H NMR (500 MHz,
CDCl3) d 2.39–2.52 (m, 2H), 2.59–2.82 (m, 4H), 4.71 (dd, J = 5.4, 1.7 Hz, 1H),
4.98–5.02 (m, 1H), 5.22 (like d, J = 10.0 Hz, 1H), 5.26 (dtd, J = 17.1, 9.8, 5.1 Hz,
1H); 13C NMR (126 MHz, CDCl3) d 23.7, 27.5, 29.1, 33.0, 62.9, 77.6, 121.3, 130.6,
169.1, 197.6; IR (CHCl3, cmꢀ1) 1786, 1730; Anal. Calcd for C10H11IO3: C, 39.24;
H, 3.62. Found: C, 39.20; H, 3.64.
Acknowledgments
9. Both the combination of DMF–H2O and its ratio (1:3) were important for the
fragmentation. The combinations such as THF–H2O and t-BuOH–H2O were not
effective.
10. (a) Hatano, M.; Takagi, E.; Arinobe, M.; Ishihara, K. J. Organomet. Chem. 2007,
692, 569–578; (b) Kobayashi, S. Synlett 1994, 689–701; (c) Kobayashi, S.;
Manabe, K. Acc. Chem. Res. 2002, 35, 209–217.
This study was financially supported by the Uehara Memorial
Foundation and a Grant-in-Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science, and Technology of
Japan.
11. Experimental procedure: The solution of 12 (99.5 mg, 0.33 mmol) and Sc(OTf)3
(167.1 mg, 0.34 mmol) in DMF (1.5 mL) and H2O (4.5 mL) was stirred at 100 °C
for 17 h. After cooling to room temperature, H2O was added, and the mixture
was extracted with ethyl acetate. The combined organic extracts were dried
over anhydrous Na2SO4, filtered, and concentrated. The crude product purified
by column chromatography on silica gel (hexane-ethyl acetate, from 3:1 to
References and notes
1. Matsuo, J.; Takeuchi, K.; Ishibashi, H. Org. Lett. 2008, 10, 4049–4052.
2. (a) Wang, J.; Soisson, S. M.; Young, K.; Shoop, W.; Kodali, S.; Galgoci, A.; Painter,
R.; Parthasarathy, G.; Tang, Y. S.; Cummings, R.; Ha, S.; Dorso, K.; Motyl, M.;
Jayasuriya, H.; Ondeyka, J.; Herath, K.; Zhang, C. W.; Hernandez, L.; Allocco, J.;
Basilio, A.; Tormo, J. R.; Genilloud, O.; Vicente, F.; Pelaez, F.; Colwell, L.; Lee, S.
H.; Michael, B.; Felcetto, T.; Gill, C.; Silver, L. L.; Hermes, J. D.; Bartizal, K.;
Barrett, J.; Schmatz, D.; Becker, J. W.; Cully, D.; Singh, S. B. Nature 2006, 441,
358–361; (b) Singh, S. B.; Jayasuriya, H.; Ondeyka, J. G.; Herath, K. B.; Zhang, C.
W.; Zink, D. L.; Tsou, N. N.; Ball, R. G.; Basilio, A.; Genilloud, O.; Diez, M. T.;
Vicente, F.; Pelaez, F.; Young, K.; Wang, J. J. Am. Chem. Soc. 2006, 128, 11916–
11920.
1:1) gave (S)-13 (38.2 mg, 0.25 mmol, 77%) as
a colorless oil and (R)-14
(6.2 mg, 32 lmol, 10%). (4S)-2-allyl-4-hydroxy-cyclohex-2-en-1-one ((S)-13):
½
a 2D4
ꢁ
ꢀ41.4 (c 0.400, CHCl3); 1H NMR (500 MHz, CDCl3) d 1.90–2.01 (m, 1H),
2.29–2.45 (m, 3H), 2.62 (dt, J = 16.5, 6.1 Hz, 1H), 2.95 (like d, J = 6.7 Hz, 2H),
4.54–4.61 (br, 1H), 5.04–5.11 (m, 2H), 5.79 (ddt, J = 17.1, 10.4, 6.7 Hz, 1H),
6.67–6.70 (m, 1H); 13C NMR (126 MHz, CDCl3) d 32.6, 33.0, 35.5, 66.6, 117.0,
134.8, 137.9, 148.0, 198.2; IR (CHCl3, cmꢀ1) 1674, 1644; HRMS (EI) calcd for
C9H12O2: 152.08373; found 152.08380.