Bromohydrin reactions of Grieco's bicyclic lactone

Article abstract of DOI:10.1016/j.tetlet.2008.09.081

The bromohydrin reaction in Grieco's bicyclic lactone 1 was reinvestigated. Two regioisomeric bromohydrins were obtained (2 and 8), and their configurations were unambiguously determined by X-ray diffraction analyses.

Full text of DOI:10.1016/j.tetlet.2008.09.081

Tetrahedron Letters 49 (2008) 6853–6855
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Tetrahedron Letters
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Bromohydrin reactions of Grieco’s bicyclic lactone
Rodolfo Tello-Aburto a, Maria Yolanda Rios a, Dale C. Swenson b, Horacio F. Olivo a,
*
a Medicinal and Natural Products Chemistry, The University of Iowa, Iowa City, IA 52242, United States
b Department of Chemistry, X-ray Diffraction Laboratory, The University of Iowa, Iowa City, IA 52242, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The bromohydrin reaction in Grieco’s bicyclic lactone 1 was reinvestigated. Two regioisomeric bromo-
hydrins were obtained (2 and 8), and their configurations were unambiguously determined by X-ray dif-
fraction analyses.
Received 29 August 2008
Revised 11 September 2008
Accepted 12 September 2008
Available online 18 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Grieco’s lactone
Bromohydrin
Grieco’s bicyclic lactone (1) has been a valuable starting mate-
rial for the syntheses of prostaglandins,1 monoterpenes,2 the anti-
biotic lactone brefeldin A,3 and also d-valerolactones.4 The
microbial synthesis of this lactone has been reported recently, in
a 200-L scale.5 Recently, Ghosh and Takayama reported an efficient
synthesis of a cyclopentyltetrahydrofuran HIV-1 protease inhibitor
from this versatile synthon.6 It was reported that addition of N-
bromosuccinimide to Grieco’s bicyclic lactone yielded a mixture
of two regioisomeric products 2 and 3 in different ratios under a
variety of reaction conditions, Figure 1.
Figure 2. Retrosynthetic analysis of aurisides.
We initially investigated the stereoselective hydroxylation of
Grieco’s bicyclic lactone during our efforts to prepare the C1–C9
fragment of the aurisides, Figure 2.4c The aurisides are marine gly-
cosylated macrolactones isolated in minute amounts from Dolabel-
la auricularia by Yamada.7
One of the reactions we investigated was the formation of bro-
mohydrins in the dimethylated lactone 4, Scheme 1. We envi-
sioned that a bromonium ion would be formed preferentially on
the exo-side of the lactone. To our surprise, we found that the ma-
jor product of the reaction was bromohydrin 5 that possessed an
endo-bromine atom and an exo-hydroxyl group.8 The structural
assignment of bromohydrin 5 was unambiguously determined by
X-ray analysis.9 The two other products were assigned as shown
in Scheme 1.
Gratifyingly, oxymercuration–demercuration of lactone 4 gave
the desired endo-hydroxyl, which was required for the synthesis
of the C1–C9 fragment of aurisides.4c Therefore, we decided to
abandon the bromohydrin route. Interestingly, we did not observe
the regioisomer type (3) assigned by Ghosh and Takayama. Based
on these results, we decided to reinvestigate the stereochemical
outcome of the bromohydrin reaction with bicyclic lactone 1.
Addition of NBS to bicyclic lactone 1 in a mixture of acetone-
water (4:1) delivered a 58:42 mixture of bromohydrins 8 and 2
in 52% combined yield, Scheme 2.10 These two bromohydrins were
chromatographically separated, and their structures unambigu-
ously assigned by single crystal X-ray analyses.9 In this case, we
observed again that the major bromohydrin had an endo-bromine
atom and the minor bromohydrin had an exo-bromine atom. Both
products resulted from formation of bromonium ion on both faces
of the olefin and regioselective nucleophilic opening of the bromo-
nium ion by water on the more accessible carbon.
Figure 1. Bromohydrin reaction.
* Corresponding author. Tel.: +1 319 335 8849; fax: +1 319 335 8766.
E-mail address: horacio-olivo@uiowa.edu (H. F. Olivo).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.081

6854
R. Tello-Aburto et al. / Tetrahedron Letters 49 (2008) 6853–6855
Scheme 1. Bromohydrin reaction of dimethylated lactone.
Scheme 2. Bromohydrin reaction of Grieco’s lactone.
Corey’s group reported that a single bicyclic bromohydrin was
obtained when the bromohydrin addition was carried out on the
corresponding bicyclic ketone, followed by Baeyer–Villiger oxida-
tion, Scheme 3.3 Indeed, only one bromohydrin 10 was obtained
when bicyclic ketone 9 was treated with NBS in acetone–water.
Baeyer–Villiger oxidation of bicyclic ketone 10 delivered bromohy-
drin lactone 2.
Scheme 4. Bromohydrin reaction under basic conditions.
Based on previous work by Corey,11 a one-pot strategy con-
sisting of hydrolysis of the bicyclic lactone 1 and treatment
with molecular bromine was attempted to prepare bromohydrin
3, Scheme 4. To our surprise, only bromohydrin 8 could be iso-
lated in low yield. In contrast, the reported iodolactonization
reaction proceeded uneventfully, and in accordance to Gulácsi
et al.12
A different approach was then taken for the synthesis of bro-
mohydrin 3, Scheme 5. Reduction of bicyclic lactone 1 with lithium
aluminum hydride gave diol 13. Double protection of diol 13 as the
TBS ether 14 was followed by selective cleavage of the primary TBS
group to deliver alcohol 15. Two-step oxidation of alcohol 15 to the
carboxylic acid 17 was accomplished by treatment with Dess Mar-
tin reagent13 to furnish aldehyde 16, followed by Lindgren–Pinnick
oxidation.14 The crude carboxylic acid 17 was submitted to our
bromination conditions to afford silyl ether 18.
Unfortunately, cleavage of the silyl protecting group even under
mild and neutral conditions, using TASF, did not afford the desired
bromohydrin 3, but the endo-epoxide 19.15,16 The stereochemistry
of the epoxide 19 was confirmed by X-ray analysis.9 Apparently,
endo-epoxide 19 is formed via trans-lactonization followed by
HBr elimination.
In summary, we have shown the correct regio- and stereochem-
istry of the bromohydrin reaction in Grieco’s bicyclic lactone 1. The
stereochemistry of bromohydrins 2 and 8, and epoxide 19 was
unambiguously determined by X-ray analyses. Comparison of the
1H and 13C NMR spectra of the bromohydrins obtained by Ghosh
and Takayama showed that they correspond to bromohydrins 2
and 8.
Scheme 5. Attempts for the preparation of bromohydrin 3.
Scheme 3. Bromohydrin reaction on bicyclic ketone.

R. Tello-Aburto et al. / Tetrahedron Letters 49 (2008) 6853–6855
6855
9. CCDC for compound 2: 699517. CCDC for compound 5: 699492. CCDC for
compound 8: 699544. CCDC for compound 19: 700139. The CCDC numbers
contain the supplementary crystallographic data for this Letter. These data can
be obtained free of charge via http://www.ccdc.cam.ac.uk/data_request/cif, by
e-mailing to data_request@ccdc.cam.ac.uk contacting the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK, fax:
+44 1223 336033.
10. (a) Bromohydrin 2: white solid; mp = 104–105 °C; Rf = 0.27, (3:2, petroleum
ether–ethyl acetate); 1H NMR (300 MHz, CDCl3): d 5.19 (1H, obs. t, J = 6.8 Hz),
4.47 (1H, m), 4.13 (1H, m), 3.37 (1H, m), 3.31 (1H, m), 2.85 (1H, dd, J = 18.6,
11.5 Hz), 2.64 (1H, dd, J = 18.6, 3.8 Hz), 2.55 (1H, ddd, J = 11.5, 6.6, 4.6 Hz), 2.21
(1H, d, J = 15.4 Hz); 13C NMR (75 MHz, CDCl3): d 177.4 (C), 84.5 (CH), 79.5 (CH),
58.3 (CH), 48.2 (CH), 38.5 (CH2), 35.9 (CH2).
Acknowledgments
We thank the College of Pharmacy at The University of Iowa for
support of this work. We also thank Professor Arun K. Ghosh (Pur-
due University) for sharing NMR copies of bromohydrins for
comparison.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.09.081.
(b) Bromohydrin 8: white solid; mp = 49–50 °C; Rf = 0.17, (3:2, petroleum
ether–ethyl acetate); 1H NMR (300 MHz, CDCl3): d 5.08 (1H, td, J = 7.2, 2.6 Hz),
4.44 (1H, ddd, J = 11.2, 5.5, 3.8 Hz), 4.20 (1H, dd, J = 7.2, 5.5 Hz), 3.35 (1H, m),
3.20 (1H, d, J = 3.7 Hz), 2.87 (1H, dd, J = 18.9, 3.7 Hz), 2.75 (1H, dd, J = 18.9,
9.9 Hz), 2.45 (1H, ddd, J = 15.0, 5.5, 2.6 Hz), 2.10 (1H, dt, J = 15.0, 6.4 Hz); 13C
NMR (75 MHz, CDCl3): d 176.8 (C), 82.6 (CH), 77.6 (CH), 58.5 (CH), 41.0 (CH),
38.4 (CH), 33.8 (CH2).
References and notes
1. (a) Corey, E. J.; Noyori, R. Tetrahedron Lett. 1970, 311–313; (b) Corey, E. J.;
Nicolaou, K. C.; Beames, D. J. Tetrahedron Lett. 1974, 2439–2440; (c) Newton, R.
F.; Roberts, S. M. Tetrahedron 1980, 36, 2163–2196.
2. (a) Grieco, P. A. J. Org. Chem. 1972, 37, 2363–2364; (b) Minns, R. A. In Organic
Synthesis; Wiley: New York, 1973; Coll. VI, pp 1037–1040.
3. Corey, E. J.; Carpino, P. Tetrahedron Lett. 1990, 31, 7555–7558.
4. (a) Clissold, C.; Kelly, C. L.; Lawrie, K. W. M.; Willis, C. L. Tetrahedron Lett. 1997,
38, 8105–8108; (b) Velazquez, F.; Olivo, H. F. Org. Lett. 2000, 2, 1931–1933; (c)
Rios, M.-Y.; Velazquez, F.; Olivo, H. F. Tetrahedron 2003, 59, 6531–6537.
5. Baldwin, C. V. F.; Wohlgemuth, R.; Woodley, J. M. Org. Process Res. Dev. 2008, 12,
660–665.
6. (a) Ghosh, A. K.; Takayama, J. Tetrahedron Lett. 2008, 49, 3409–3412; (b)
Corrigendum: Tetrahedron Lett. 2008, 49, 6269. doi: 10.1016/j.tetlet.2008.
08.053
11. Corey, E. J.; Mann, J. J. Am. Chem. Soc. 1973, 95, 6832–6833.
12. Tömösközi, I.; Gruber, L.; Gulácsi, E. Tetrahedron Lett. 1985, 26, 3141–3144.
13. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
14. (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888–890; (b) Bal, B.
S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37, 2091–2096.
15. endo-Epoxide 19: colorless solid; Rf = 0.34 (100% ethyl acetate); 1H NMR
(300 MHz, CDCl3): d 4.99 (1H, t, J = 7.1 Hz), 3.66 (1H, br s), 3.63 (1H, br s), 3.07–
3.00 (1H, m), 2.78–2.64 (2H, m), 2.49 (1H, d, J = 16.3 Hz), 2.12 (1H, ddd, J = 16.3,
7.0, 1.4 Hz), 1.64 (1 H, br s); 13C NMR (75 MHz, CDCl3): d 176.3 (C), 83.5 (CH),
60.9 (CH), 60.2 (CH), 40.2 (CH), 34.5 (CH2), 30.3 (CH2). HRMS (EI) calculated for
(C7H8O3) m/z 140.0473, found m/z 140.0469.
16. We epoxidized bicyclic lactone 1 with m-CPBA. Epoxidation of bicyclic lactone
1 furnished endo- and exo-epoxides 19 and 20 in a 2:1 ratio in 92% overall
yield. These two epoxides were separated by column chromatography.
7. (a) Sone, H.; Kigoshi, H.; Yamada, K. J. Org. Chem. 1996, 61, 8956–8960; For our
formal synthesis of aurisides, see: (b) Tello-Aburto, R.; Olivo, H. F. Org. Lett.
2008, 10, 2191–2194.
8. Bromohydrin 5: white solid; mp = 136–137 °C; Rf = 0.44 (1:1, petroleum ether–
ethyl acetate), 0.35 (9:1 CH2Cl2–ethyl acetate). 1H NMR (300 MHz, CDCl3) d
5.12 (1H, m), 4.65 (1H, app. t, J = 3.5 Hz), 4.19 (1H, d, J = 4.8 Hz), 3.08 (1H, t,
J = 5.5 Hz), 2.82 (1H, br s), 2.69 (1H, dt, J = 15.6, 3.6 Hz), 2.34 (1H, ddd, J = 15.6,
7.6, 1.5 Hz), 1.49 (3H, s), 1.35 (3H, s); 13C NMR (75 MHz, CDCl3) d 182.0 (C), 81.3
(CH), 80.4 (CH), 55.4 (CH), 54.4 (CH), 43.7 (C), 38.3 (CH2), 27.5 (CH3), 19.2 (CH3).
HRMS (EI) calculated for (C9H13BrO3) m/z 250.0028, found m/z 250.0039.