Synthesis of β-hydroxy-δ-trichloromethyl-δ-valerolactones by intramolecular samarium/ytterbium diiodide-mediated Reformatsky reaction

Article abstract of DOI:10.1016/j.tetlet.2012.11.146

The synthesis of α-methyl-β-hydroxy-δ-trichloromethyl- δ-valerolactone was achieved by an intramolecular Reformatsky reaction. The cyclisation was effected by samarium diiodide or (for the first time) ytterbium diiodide. The diastereoselectivity of the reaction corresponds to earlier investigations by Molander. Consecutive stereoselective reactions during the esterification to the Reformatsky precursor 1,1,1-trichloropent-4-en-2-yl 2-bromopropanoate and in the Reformatsky reaction itself led to (3RS,4RS,6SR)-4-hydroxy-3-methyl-6-(trichloromethyl)tetrahydro-2H-pyran-2-one (3a) as the major formed diastereomer. The influence of the orientation of the substituents in the transition state is discussed.

Full text of DOI:10.1016/j.tetlet.2012.11.146

Tetrahedron Letters 54 (2013) 921–924
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of b-hydroxy-d-trichloromethyl-d-valerolactones by intramolecular
samarium/ytterbium diiodide-mediated Reformatsky reaction
⇑
Thies M. Schulze, Jörg Grunenberg, Stefan Schulz
Technische Universität Braunschweig, Institut für Organische Chemie, Hagenring 30, 38106 Braunschweig, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a-methyl-b-hydroxy-d-trichloromethyl-d-valerolactone was achieved by an intramolec-
Received 28 August 2012
Revised 29 November 2012
Accepted 30 November 2012
Available online 7 December 2012
ular Reformatsky reaction. The cyclisation was effected by samarium diiodide or (for the first time)
ytterbium diiodide. The diastereoselectivity of the reaction corresponds to earlier investigations by
Molander. Consecutive stereoselective reactions during the esterification to the Reformatsky pre-
cursor 1,1,1-trichloropent-4-en-2-yl 2-bromopropanoate and in the Reformatsky reaction itself led to
(
3RS,4RS,6SR)-4-hydroxy-3-methyl-6-(trichloromethyl)tetrahydro-2H-pyran-2-one (3a) as the major
Keywords:
Lactones
formed diastereomer. The influence of the orientation of the substituents in the transition state is
discussed.
Intramolecular Reformatsky reaction
Samarium diiodide
Ytterbium diiodide
Trichloromethyl group
Kinetic resolution
Ó 2012 Elsevier Ltd. All rights reserved.
Substituted lactones have been employed as important precur-
sors in the total synthesis of a wide variety of natural products.
Our synthesis was inspired by a synthetic route reported by Sa-
1
–3
want and Jennings for intermediate 7, needed in the synthesis of
3
Our recent investigations into the structure and bioactivity of poly-
chlorinated polyketides led us to investigate possible synthetic
routes towards b-hydroxy-d-trichloromethyl-valerolactone 3, a
member of a compound class only rarely investigated. The initial
cyclisation approach by intramolecular esterification of the b,d-
dihydroxy acid 1 or transesterification of the corresponding ester
diospongins A and B (Scheme 2).
Our approach utilises trichloromethylhomoallyl alcohol 8 that
had to be transformed into ester 9 and finally via the intramolecu-
lar Reformatsky reaction into lactone 3 (Scheme 3). Intermediate 8
was synthesised as a racemate by the Grignard addition of com-
mercially available allylmagnesium bromide solution to freshly
distilled chloral (10), a more convenient variation of several previ-
2
was frustrated by the low reactivity of the d-hydroxyl group,
1
2
which appears to be caused by the high steric demand and elec-
ously reported syntheses of alcohol 8 (Scheme 4).
4
tron-withdrawing properties of the vicinal trichloromethyl group.
The subsequent esterification with 2-bromopropionyl bromide
3
In addition, the b-hydroxyl group has a high tendency to eliminate,
(11) and pyridine exhibited a varying degree of diastereoselectiv-
often leading to the formation of the
a
,b-unsaturated lactone 4
ity, depending on the reaction conditions. Variation of the reaction
temperature and the excess of acyl bromide and pyridine used
indicated that the reaction is under kinetic control (Table 1). The
highest diastereomeric excess of (RS)-1,1,1-trichloropent-4-en-2-yl
(Scheme 1). While the cyclisation of b,d-dihydroxycarboxylic acids
2
,5
is a common procedure in the synthesis of b-hydroxylactones, it
has rarely been described with d-trichloromethyl substituted hy-
6
,7
droxy acids,
and the high sensitivity of the reaction towards
6
elimination has been noted. In order to circumvent this problem,
we revised our approach by use of a C–C bond formation reaction
between C-3 and C-4 of the target lactone. A samarium diiodide
O
1
6
O
OH OH
O
3
4
8
,9
RO
CCl3
mediated Reformatsky reaction was used as the key step. This
type of reaction has already proven its usefulness in a variety of
Cl3C
OH
1
R = H
3
1
0
2 R = tBu
lactonisations, some of which lead to natural products like clav-
O
ulactone or pederin.11
p-TsOH
O
Cl C
3
4
⇑
Corresponding author. Tel.: +49 531 391 7353; fax: +49 531 391 5272.
E-mail address: stefan.schulz@tu-bs.de (S. Schulz).
Scheme 1. Direct lactonisation of d-hydroxycarboxylates 1 or 2.
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.146

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22
T. M. Schulze et al. / Tetrahedron Letters 54 (2013) 921–924
0
O
O
Br
11. Accordingly, (S,R )-12 can be accessed using (R)-14 or 11 in-
stead of the (S)-enantiomer. This reaction is an example for the ki-
netic resolution
1
2
) bromoacetyl bromide,
pyridine, CH Cl
OH
2
2
1
3
of alcohol 8 and the counterpart to the
previously reported kinetic resolution of rac-11 and rac-14 with
) OsO , NaIO ,
O
4
4
dioxane/H O
5
2
6
1
4
different alcohols.
The enantiomers of the kinetically disfavoured diastereomer 13
could potentially be synthesised in the same way, but with de-
creased yield and purity, only. Consequently, an approach starting
from enantiopure 8 was developed.
O
SmI , CH Cl , 0°C
O
2
2
2
OH
32 %
7
First, the enantiopure aldehyde 15 was synthesised from com-
mercially available (R)-4-(trichloromethyl)oxetan-2-one according
to a procedure previously reported by Tennyson. The aldehyde
Scheme 2. Lactone synthesis by Savant and Jennings.3
15
was then methylenated using the Tebbe reagent, because a Wit-
tig-type methylenation proved to be inferior due to the sensitivity
of the trichloromethyl group towards strong bases (Scheme 5).
O
O
16
O
OH
Br
O
Then the triethylsilyl group was cleaved off using acetate-buffered
Cl C
17
3
Cl C
O
Cl C
OH
3
3
tetrabutylammonium fluoride to yield (R)-8. The subsequent
8
9
3
esterification of (R)-8 to the disfavoured (R)-1,1,1-trichloropent-
0
4
-en-2-yl (R )-2-bromopropanoate 13 was performed by a modi-
Scheme 3. Synthetic plan to the lactone 3.
18
fied Steglich esterification using EDC hydrochloride and DMAP
in dichloromethane, providing the ester in 44% yield.
1
9
The oxidative cleavage of the terminal double bond in 12/13 to
aldehyde 6 by ozonolysis proceeded smoothly and quantita-
tively, although subsequent flash chromatography led to partial
MgBr
O
20
OH
Cl C
H
3
Et O, 0°C, 87 % Cl C
2
3
10
rac-8
decomposition of the product to the
a,b-unsaturated elimination
product 18 (Scheme 6). This problem was reduced by high flow
rates and resulting short column retention times, so that largely
pure 9 could be isolated in 85% yield. Undesired by-products can
alternatively be removed by evaporation under high vacuum, but
this led to a less pure product which was detrimental to the yield
in the subsequent lactonisation.
O
Br
O
O
Br
11
O
+
O
Br
Br
py, CH Cl , 92 %
Cl C
3
Cl C
3
2
2
rac-12
d.r. = 76:24
rac-13
The lactonisation was performed in dry tetrahydrofuran using
2
1
at least 3 equivalents of samarium diiodide. A commercially
available stock solution of the reagent in THF was used. The yield,
however, was poor at 29%, although similar to the one reported by
O
Cl
3
Br
O(S)
O(S)
Savant and Jennings in the synthesis of 7. Our initial hypothesis
1
4
was a competing reaction of samarium(II) with the trichloromethyl
group, so a less reactive lanthanide was tested. Ytterbium(II) has a
O
rac-8
O
+
Br
Br
py, CH Cl , 54 %
2
2
Cl C(R)
Cl3C(S)
3
22
lower standard potential than samarium (ꢀ1.15 V vs ꢀ1.55 V),
(
R,S')-12
(S,S')-13
which led to the assumption that it might be less prone to side
reactions. Ytterbium diiodide, freshly prepared from ytterbium
d.r. = 78:22
8
chunks and diiodomethane, was then used. While the yield could
Scheme 4. Synthesis of the Reformatsky precursors 12 and 13.
not be significantly improved, this reaction marks, to the best of
our knowledge, the first time that ytterbium has been used as
the active reagent in a Reformatsky reaction (Scheme 6).
(
SR)-2-bromopropanoate (rac-12) was 53% (dr 76:24), and was
achieved with 5 equivalents of acyl bromide and pyridine at
78 °C. Most of the minor diastereomer (RS)-1,1,1-trichloropent-
-en-2-yl (RS)-2-bromopropanoate (rac-13) was removed by a sin-
While stereoselectivity can be induced in the Reformatsky reac-
2
3
ꢀ
tion by chiral additives or catalysts, Molander has shown that the
intramolecular samarium diiodide-mediated Reformatsky reaction
of chiral precursors often exhibits an intrinsic diastereoselectivi-
4
gle column chromatography, yielding the favoured diastereomer
rac-12 in 83% de (Scheme 4). The combined yield over both diaste-
reomers was 92%. This route provided a short and easy access to
2
4
ty. Bulky substituents at C-6 of the target valerolactone favour
the formation of the 4,6-anti product via the chair-like transition
states 19a and 19b (Scheme 8). In these cases the substituent at
0
the favoured enantiomer (R,S )-12 when a substoichiometric
amount of enantiomerically pure acyl halide (S)-14 was used,
although the yield was lower with chloride 14 than with bromide
OTES
Tebbe rea.
THF, 51 %
OTES TBAF, AcOH
Cl C
O
Cl C
3
3
Table 1
THF, 43 %
Stereoselectivity in the esterification of alcohol 8
15
16
Equiv
Temp (°C)
13/12
O
HO
2
5
0
0
0
64:36
67:33
67:33
76:24
70:30
Br
17
O
EDC·HCl,
DMAP
OH
O
Br
1
0
Cl C
5
ꢀ78
3
Cl C
CH Cl , 44 %
3
a
2
2
5
ꢀ78
(R)-8
(R,R')-13
Equiv: equivalents of compound 11.
a
DMAP instead of pyridine.
0
Scheme 5. Synthesis of the disfavored (R,R )-13 enantiomer.

T. M. Schulze et al. / Tetrahedron Letters 54 (2013) 921–924
923
O
O
O
O
Table 2
Stereoselectivity in the Reformatsky lactonisation
Br
O3, CH Cl /MeOH
2
2
Br
O
Substrate dra
Temp (°C)
3a/3b
(3a + 3b)/(3c + 3d)
Cl C
quant./
Cl C
3
3
8
5% (flash chrom.)
12/13
9
91:9
ꢀ40
ꢀ40
0
ꢀ40
78:22
76:24
73:27
48:52
79:21
72:28
78:22
79:21
9
9
5
1:9
1:9
2:48
A) SmI , THF, 29 %
O
2
a
B) YbI , THF, 30 %
rac-12/rac-13.
2
O
Cl C
3
O
Cl C
OH
18
3
3
Table 3
Quantum-mechanical calculated energy differences (rows—columns) of diastereo-
mers 3a–d (M06-2X/6-311G(d,p)26
Scheme 6. Formation of trichloromethyl lactone 3 via Reformatsky reaction.
)
kJ/mol
3b
3d
3c
O
O
3a
4.65
8.30
3.64
8.86
4.22
0.58
1
3
.35
1.33
CH
CH3
3b
3d
O
H
O
H2.59
H
2.73
Cl C
.31OH Cl C
OH
3
3
H4
H
H4.12
5
.16
5.09
H
H
H
H
2.51
2
.07
2
.69
2.2
figured diastereomer 3a, with a ratio of 3a/3b between 0.94 and
.57 depending on the reaction conditions (Table 2). In general, a
3
3
a
3b
reduction of the reaction temperature was beneficial for the selec-
tivity of the reaction, which implies at least partial kinetic control.
This is consistent with the transition state model proposed by
Scheme 7. Nuclear overhauser interactions between protons in the two major
diastereomers of lactone 3.
2
4
Molander, as the syn-configured diastereomers result from a
transition state in which the methyl group at C3 is in an equatorial
position. Furthermore, quantum-mechanical calculations applying
O
26
density functional theory at the M06-2X/6-311G(d,p) level (as
Cl C
Cl C
O
3
O
3
O
HO
2
7
O
Sm
implemented in the GAUSSIAN 09 program ) indicate that the 3,4-
O
O
Cl3C
OH
OH
syn diastereomer 3a is thermodynamically more stable than the
1
9a "Z" enolate
3a
3
,4-anti diastereomer 3b by 4.65 kJ/mol (Table 3). Thus, both ki-
O
netic and thermodynamic factors appear to favour diastereomer
Cl C
Cl C
3
O
3
O
O
HO
3
a over diastereomer 3b.
O
Sm
O
O
Cl C
3
Interestingly, when the diastereomerically enriched aldehyde
1
9b "E" enolate
3b
(RS,SR)-9 is used, the ratio of 3a/3b tends to be higher compared
O
to the racemic aldehyde. While this implies an influence of the
configuration of the starting material on the geometry of the eno-
late in the transition state, further investigations are needed to
confirm a chirality transfer. Although not all experiments were re-
peated with ytterbium iodide instead of samarium iodide, the ste-
reochemical results were similar with both reagents.
Cl C
O
Cl C OH
3
Sm
3
O
O
O
O
O
Cl C
OH
OH
3
1
9c "Z" enolate
3c
O
OH
Cl C O Sm
Cl C
3
3
O
O
O
Even though they show no significant separation on TLC, diaste-
reomers 3a–d have been separated by careful column chromatog-
raphy, with 3a eluting first, followed by 3d and 3b and finally 3c.
In conclusion, the hitherto unreported trichloromethyl valero-
lactone 3 has been synthesised with some degree of diastereoselec-
tivity, and an enantioselective synthesis of key intermediate 8 and
the isomers of 12 and 13 has been established. Valerolactone 3
may become a precursor in novel total syntheses of natural prod-
ucts due to the ability of the trichloromethyl group to be trans-
formed into a variety of related functional groups,7 while both
the hydroxyl group and the carboxyl group are open to redox
O
O
Cl C
3
19d "E" enolate
3d
Scheme 8. Transition state geometry of the enolates 19a–d.
C-6 can assume an equatorial position, while the transition states
9c and 19d are higher in energy due to 1,3-diaxial repulsion be-
tween the trichloromethyl group and both samarium-coordinated
oxygen atoms, and are thus disfavoured. This was confirmed here
with trichloromethyl-substituted lactones 3a–d, with 4,6-anti-con-
figured diastereomer 3a being the major product as determined by
1
2
8
chemistry.
1
Acknowledgements
NMR ( H coupling constants and nuclear overhauser effects (NOE),
Scheme 7).
Parts of this work were funded by the Deutsche Forschungs-
gemeinschaft (DFG). T.S. is grateful for the financial support.
Much less investigated is the influence of transition state geom-
etry and configuration of the starting material on the configuration
of the substituent at C-3 of the target lactone. While a degree of
diastereoselectivity has already been observed for this chiral centre
Supplementary data
in similar cyclisations,2
4,25
the full relative configuration of the
respective lactones has not previously been elucidated. For this
reason, we have determined the relative configuration for all dia-
stereomers of lactone 3 using NMR spectroscopy as described
above. Our results show a moderate preference for the 3,4-syn con-
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.11.
146. These data include MOL files and InChiKeys of the most
important compounds described in this article.

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T. M. Schulze et al. / Tetrahedron Letters 54 (2013) 921–924
1
6. Tori, M.; Hisazumi, K.; Wada, T.; Sono, M.; Katsuyuki, Nakashima Tetrahedron:
References and notes
Asymmetry 1999, 10, 961–971.
1
7. Debenham, J. S.; Rodebaugh, R.; Fraser-Reid, B. J. Org. Chem. 1997, 62, 4591–
1
.
For recent examples see: Snider, B. B.; Song, F. Org. Lett. 2001, 3, 1817–1820;
Yoshimura, T.; Yakushiji, F.; Kondo, S.; Wu, X.; Shindo, M.; Shishido, K. Org. Lett.
4600.
18. Neises, B.; Steglich, W. Angew. Chem., Int. Ed. 1978, 17, 522–524.
19. Patel, J.; Hoyt, J. C.; Parry, R. J. Tetrahedron 1998, 54, 15927–15936.
20. Molander, G. A.; Cameron, K. O. J. Org. Chem. 1993, 58, 5931–5943.
21. Takemura, T.; Nishii, Y.; Takahashi, S.; Kobayashi, J.; Nakata, T. Tetrahedron
2
006, 8, 475–478; Stewart, A. M.; Meier, K.; Schulz, B.; Steinert, M.; Snider, B. B.
J. Org. Chem. 2010, 75, 6057–6060.
2
3
4
5
.
.
.
.
Nakamura, R.; Tanino, K.; Miyashita, M. Org. Lett. 2005, 7, 2929–2932.
Sawant, K. B.; Jennings, M. P. J. Org. Chem. 2006, 71, 7911–7914.
Chauvin, R.; Kagan, H. B. Chirality 1991, 3, 242–253.
For a variety of different methods see for example: Sliskovic, D. R.; Picard, J. A.;
Roark, W. H.; Roth, B. D.; Ferguson, E.; Krause, B. R.; Newton, R. S.; Sekerke, C.;
Shaw, M. K. J. Med. Chem. 1991, 34, 367–373; Evans, D. A.; Carter, P. H.; Carreira,
E. M.; Prunet, J. A.; Charette, A. B.; Lautens, M. Angew. Chem., Int. Ed. 1998, 37,
2
002, 58, 6359–6365.
2. Bowman, L. J.; Izod, K.; Clegg, W.; Harrington, R. W. Organometallics 2007, 26,
646–2651.
2
2
2
3. Cozzi, P. G. Angew. Chem., Int. Ed. 2006, 45, 2951–2954; Fernández-Ibáñez, M.
Á.; Maciá, B.; Minnaard, A. J.; Feringa, B. L. Angew. Chem., Int. Ed. 2008, 47,
1
317–1319; Wolf, C.; Moskowitz, M. J. Org. Chem. 2011, 76, 6372–6376.
4. Molander, G. A.; Etter, J. B.; Harring, L. S.; Thorel, P. J. J. Am. Chem. Soc. 1991,
13, 8036–8045.
5. Oh, H.-S.; Yun, J.-S.; Nah, K.-H.; Kang, H.-Y.; Sherman, D. H. Eur. J. Org. Chem.
007, 3369–3379; Fukui, H.; Shiina, I. Org. Lett. 2008, 10, 3153–3156.
2
354–2359; Wolberg, M.; Hummel, W.; Wandrey, C.; Müller, M. Angew. Chem.,
2
2
Int. Ed. 2000, 39, 4306–4308; Bonini, C.; Cazzato, C.; Cernia, E.; Palocci, C.; Soro,
S.; Viggiani, L. J. Mol. Catal. B 2001, 16, 1–5; Zakrzewski, P.; Lau, C. K. Synlett
1
2
003, 2, 215–218; Greenberg, W. A.; Varvak, A.; Hanson, S. R.; Wong, K.; Huang,
2
H.; Chen, P.; Burk, M. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5788–5793.
Shimizu, M.; Ishii, K.; Fujisawa, T. Chem. Lett. 1997, 26, 765–766.
Tiseni, P. S.; Peters, R. Angew. Chem., Int. Ed. 2007, 46, 5325–5328.
Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102, 2693–2698.
Reformatsky, S. Ber. Dtsch. Chem. Ges. 1887, 20, 1210–1211.
2
2
6. Zhao, Y.; Truhlar, D. Theor. Chem. Acc. 2008, 120, 215–241.
6
7
8
9
.
.
.
.
7. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.;
Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.;
Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven,
T., ; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.;
Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.;
Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.;
Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas,
Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. GAUSSIAN 09 Revision A.1;
GAUSSIAN, Inc.: Wallingford, CT, 2009.
1
1
1
0. Ocampo, R.; Dolbier, W. R., Jr. Tetrahedron 2004, 60, 9325–9374.
1. Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. Rev. 2004, 104, 3371–3404.
2. Bishop, D. C.; Meacock, S. C. R.; Williamson, W. R. N. J. Chem. Soc. C 1966, 670–
6
73; Salomon, R. G.; Ghosh, S.; Jackson, D. K.; Benson, R. E. Org. Synth. 1990,
Coll. Vol. 7, 177ff; Tan, X.-H.; Shen, B.; Deng, W.; Zhao, H.; Liu, L.; Guo, Q.-X. Org.
Lett. 2003, 5, 1833–1835; Blanchet, J.; Zhu, J. Tetrahedron Lett. 2004, 45, 4449–
4
452.
1
1
3. Somfai, P. Angew. Chem., Int. Ed. 1997, 36, 2731–2733.
4. Camps, P.; Pérez, F.; Soldevilla, N. Tetrahedron: Asymmetry 1997, 8, 1877–1894;
Durst, T.; Koh, K. Tetrahedron Lett. 1992, 33, 6799–6802.
1
5. Tennyson, R. L.; Cortez, G. S.; Galicia, H. J.; Kreiman, C. R.; Thompson, C. M.;
Romo, D. Org. Lett. 2002, 4, 533–536; Yang, H. W.; Romo, D. Tetrahedron 1999,
28. Eisenbraun, E. J.; Corey, E. J.; Hamanaka, E. Org. Synth. 1965, 45, 28ff.
55, 6403–6434.