Alkyl C-O ring cleavage of bicyclic β-lactones with normant reagents: Synthesis of a merck IND intermediate

Article abstract of DOI:10.1021/ol070572p

Highly diastereoselective Cu(I)-mediated, bicyclic β-lactone ring cleavage reactions with either alkyl or aryl cuprates proceeded with inversion of stereochemistry to give optically active trans-substituted cyclopentanes and cyclohexanes. Optimization of

Full text of DOI:10.1021/ol070572p

ORGANIC
LETTERS
2007
Vol. 9, No. 11
2111-2114
Alkyl C
−O Ring Cleavage of Bicyclic
â
-Lactones with Normant Reagents:
Synthesis of a Merck IND Intermediate
Wei Zhang, Andrea S. Matla, and Daniel Romo*
Department of Chemistry, Texas A&M UniVersity, P.O. Box 30012,
College Station, Texas 77842-3012
romo@tamu.edu
Received March 7, 2007
ABSTRACT
Highly diastereoselective Cu(I)-mediated, bicyclic â-lactone ring cleavage reactions with either alkyl or aryl cuprates proceeded with inversion
of stereochemistry to give optically active trans-substituted cyclopentanes and cyclohexanes. Optimization of typically problematic aryl cuprate
additions was made possible by minimization of a competing bromide-induced ring cleavage process. The utility of this process was demonstrated
by an efficient synthesis of a Merck investigational new drug (IND) intermediate for an anti-HIV CCR5 antagonist.
The recent development of various asymmetric methods for
the syntheses of â-lactones has enhanced the utility of these
useful intermediates in organic synthesis.1 This has been
accompanied by simultaneous efforts to expand the repertoire
of transformations possible with â-lactones.2 The inherent
reactivity of â-lactones derives from the strained four-
membered ring and the dual reactivity of â-lactones as
electrophiles via acyl C-O or alkyl C-O cleavage provides
further flexibility for their use in synthetic endeavors (Figure
1). The dual reactivity of â-lactones is explained well by
soft-hard acid base theory with hard nucleophiles leading
to acylation and soft nucleophiles leading to alkylation.
As part of our efforts to develop asymmetric routes to
â-lactones, we developed an asymmetric intramolecular
nucleophile-catalyzed aldol-lactonization (NCAL) process
that efficiently generates a variety of multifunctionalized
bicyclic â-lactones from acid aldehydes (Scheme 1)3 and
more recently bicyclic and tricyclic â-lactones from keto
acids.4 With access to these systems, we have also been
studying their reactivity in alkyl C-O cleavage reactions
with soft nucleophiles.5 One transformation of interest was
stereochemical invertive ring cleavage of bicyclic â-lactones
leading stereospecifically to â-substituted cyclopentyl and
(1) For reviews, see: (a) Pommier, A.; Pons, J-M. Synthesis 1993, 441.
(b) Wang, Y.; Tennyson, R. L.; Romo, D. Heterocycles 2004, 64, 605. For
more recent advances, see: (c) Zhu, C.; Shen, X.; Nelson, S. G. J. Am.
Chem. Soc. 2004, 126, 5352. (d) Wilson, J. E.; Fu, G. Agnew. Chem., Int.
Ed. 2004, 43, 6358. (e) Calter, M. A.; Tretyak, O. A.; Flaschenriem, C.
Org. Lett. 2005, 7, 1809. (f) Oh, S. H.; Cortez, G. S.; Romo, D. J. Org.
Chem. 2005, 70, 2835. (g) Gnanadesikan, V.; Corey, E. J. Org. Lett. 2006,
8, 4943. (h) Kramer, J. W.; Lobkovsky, E. B.; Coates, G. W. Org. Lett.
2006, 8, 3709.
(2) For reviews, see: (a) Pommier, A.; Pons, J.-M. Synthesis 1995, 729.
(b) Yang, H. W.; Romo, D. Tetrahedron 1999, 55, 6403. For selected recent
examples, see: (c) Donohoe, T. J.; Sintim, H. O.; Sisangia, L.; Harling, J.
D. Angew. Chem., Int. Ed. 2004, 43, 2293. (d) Getzle, Y. D. Y. L.; Kundnani,
V.; Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2004, 126, 6842.
(e) Calter, M. A.; Tretyak, O. A.; Flaschenriem, C. Org. Lett. 2005, 7, 1809.
(f) Mitchell, T. A.; Romo, D. Heterocycles 2005, 66, 627. (g) Shen, X.;
Wasmuth, A. S.; Zhao, J.; Zhu, C.; Nelson, S. G. J. Am. Chem. Soc. 2006,
128, 7438. (h) Henry-Riyad, H.; Lee, C.; Purohit, V. C.; Romo, D. Org.
Lett. 2006, 8, 4363. (i) Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8, 1717.
Figure 1. Dual reactivity of â-lactones toward nucleophilic ring
cleavage.
10.1021/ol070572p CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/04/2007

Scheme 1. Enantioselective Synthesis of Bicyclic â-Lactones
via the Nucleophile-Catalyzed Aldol Lactonization (NCAL)
Process
Table 1. Stereochemical Invertive Ring Cleavage of [3.2.0]
Bicylic â-Lactone (+)-1 with Various Alkyl Cuprates
cyclohexyl carboxylic acids, useful building blocks for
natural and unnatural product synthesis. Pioneering studies
of this process by Fujisawa, Normant, and subsequently
Vederas focused primarily on cuprate additions to monocy-
clic â-lactones.6 In these and more recent studies,7 aryl
cuprate addition was often compromised by lower conversion
and 1,2-addition.8 Herein, we report the reactivity of both
alkyl and aryl cuprates with bicyclic â-lactones and the
important impact of MgBr2 concentration on the efficiency
of addition, an observation previously noted by Vederas6g
but apparently overlooked in more recent studies.9
a Conditions: RMgBr (6.0 equiv), CuBr‚DMS (3.0 equiv), TMSCl (1.5
equiv), THF, -42 to -5 °C, 2 h. b i-PrMgCl was employed instead of
i-PrMgBr. c The reaction was warmed to 10 °C over 4 h. d Yields refer to
isolated (silica gel), purified product. e dr >19:1, minor diastereomers could
1
not be detected in crude reaction mixtures (500 MHz H NMR).
We intiated our studies with bicyclic â-lactone (+)-11f and
screened a variety of alkyl cuprates under standard condi-
tions.10 Starting with methyl cuprate, it was determined that
3.0 equiv of cuprate were necessary for optimal conversion.
Use of only 1.5 equiv led to incomplete reaction even upon
warming to ambient temperature (Table 1, entry 1). Interest-
ingly, reaction with i-PrMgCl-derived cuprate was complete
within 30 min at -42 °C (Table 1, entry 2). When the bulky
t-BuMgBr-derivedcupratewasemployed, onlymodestconver-
sion (25%) was observed even when the reaction was warmed
to ambient temperature (Table 1, entry 3). While use of
BnMgBr-derived cuprate required warming to 10 °C for com-
plete consumption of starting material, this cuprate gave the
most efficient conversion to alkylated product (Table 1, entry
4).
Two results mirror those previously observed during
studies of additions to monocyclic â-lactones (Scheme 2).
Scheme 2. Divergent Reactivity with Vinyl and Allyl
Cuprates
(3) (a) Cortez, G. S.; Tennyson, R. L.; Romo, D. J. Am. Chem. Soc.
2001, 123, 7945. (b) Cortez, G. S.; Oh, S. H.; Romo, D. Synthesis 2001,
1731. (c) See also ref 1f.
(4) Riyad, H.; Lee, C. S.; Purohit, V.; Romo, D. Org. Lett. 2006, 8, 4363.
(5) For additions of heteroatom nucleophiles to bicyclic â-lactones, see:
(a) Yokota, Y.; Cortez, G. S.; Romo, D. Tetrahedron 2002, 58, 7075. For
other examples of additions to monocyclic-â-lactones, see: (b) ref 2. (c)
Nelson, S. G.; Spencer, K. L; Cheung, W. S.; Mamie, S. J. Tetrahedron
2002, 58, 7081.
First, the allylmagnesium chloride-derived cuprate led to
exclusive double 1,2-addition providing keto diol (+)-3.7a,11
Second, use of vinyl cuprate gave a tandem 1,2/1,4 addition
leading to ketone (-)-4 in high yield.7b
(6) (a) Normant, J. F.; Alexakis, A.; Cahiez, G. Tetrahedron Lett. 1980,
21, 935. (b) Sato, T.; Kawara, T.; Kawashima, M.; Fujisawa, T. Chem.
Lett. 1980, 571. (c) Sato, T.; Kawara, T.; Nishizawa, A.; Fujisawa, T.
Tetrahedron Lett. 1980, 21, 3377. (d) Fujisawa, T.; Sato, T.; Kawara, T.;
Ohashi, K. Tetrahedron Lett. 1981, 22, 4823. (e) Sato, T.; Naruse, K.;
Fujisawa, T. Tetrahedron Lett. 1982, 23, 3587. (f) Sato, T.; Itoh, T.; Hatori,
C.; Fujisawa, T. Chem. Lett. 1983, 1391. (g) Arnold, L. D.; Kalantar, T.
H.; Vederas, J. C. J. Am. Chem. Soc. 1985, 107, 7105. (h) Arnold, L. D.;
Kalantar, T. H.; Vederas, J. C. J. Am. Chem. Soc. 1987, 109, 4649. (i)
Kawashima, M.; Sato, T.; Fujisawa, T. Tetrahedron 1989, 45, 403.
(7) (a) Nelson, S. G.; Wan, Z.; Stan, M. A. J. Org. Chem. 2002, 67, 4680.
(b) Smith, N. D.; Wohlrab, A. M.; Goodman, M. Org. Lett. 2005, 7, 255.
(8) The report from the Goodman group (ref 7b) made extensive use of
chloro Grignard-derived cuprates but no rationalization was provided.
(9) For recent reports of invertive cleavage of â-lactones with various
nucleophiles, see: (a) Castagnani, R.; De Angelis, F.; De Fusco, E.;
Giannessi, F.; Misiti, D.; Meloni, D.; Tinti, M. O. J. Org. Chem. 1995, 60,
8318. (b) Bernabei, I.; Castagnani, R.; De angelis, F.; De Fusco, E.;
Giannessi, F.; Misiti, D.; Muck, S.; Scafetta, N.; Tinti, M. O. Chem. Eur.
J. 1996, 2, 826. (c) Nelson, S. G.; Spencer, K. L. Angew. Chem., Int. Ed.
2000, 39, 1323. (d) Reference 5.
We then studied aryl cuprates beginning with phenyl
cuprate and again found that stoichiometry was crucial for
optimal conversion. However, application of the optimized
conditions developed for alkyl cuprate additions gave only
poor yields of the phenyl adduct 5a, which was isolated as
ester (+)-6a following esterification with diazomethane
(Table 2). After careful separation and analysis, a major
byproduct was identified as the somewhat unstable â-bromo
acid 7, which was more readily isolated after esterification
to provide methyl ester (+)-8.12 Unreacted starting material
could also be recovered; however, 1,2-addition was not
observed. By increasing the amount of cuprate to 5.0 equiv,
conversion was improved and ester (+)-6a was isolated in
(10) Nelson previously employed similar conditions for additions to
monocyclic-â-lactones, see ref 7a.
(11) In this instance, the dioxolane was prone to hydrolysis during
reaction workup.
2112
Org. Lett., Vol. 9, No. 11, 2007

providing ester (+)-8 as a single diastereoisomer in nearly
quantitative yield after esterification (Scheme 3). It should
Table 2. Stereochemical Invertive â-Lactone Cleavage with
Phenyl Cupratea
Scheme 3. â-Lactone Opening with MgBr2‚OEt2 Leading to
Bromide (+)-8
cuprate % yieldd % yieldd,e
entry
PhM
CuX
(equiv)
(+)-6a
(+)-8
be noted that bromide (+)-8 is itself a useful synthon bearing
a protected ketone and two electrophilic sites.
1
2
3
4
5
6
7b
8c
PhMgBr CuBr‚DMS
PhMgBr CuBr‚DMS
PhMgBr CuBr‚DMS
PhLi
PhLi
PhLi
3.0
5.0
8.0
3.0
3.0
3.0
5.0
5.0
<10
33
35
0
<5
0
25
30
36
0
0
0
We next studied a cyclohexyl-fused â-lactone (+)-9.1f In
analogy to results with cyclopentyl systems, this substrate
was readily cleaved with Normant-type reagents under
identical conditions to give both alkyl- and aryl-substituted
products 10 (Table 3). To simplify the purification process,
CuI
CuI, PBu3
CuCN
PhMgCl CuBr‚DMS
PhMgCl CuCl
72
61
18
0
a Typical conditions: 0.03 M, 3.0-8.0 equiv of cuprate, 8.0 equiv of
Me2S, TMSCl (1.5 equiv), -42 to 10 °C, 6-10 h. b Typical conditions
with the exception that the reaction was run at 0.02 M with 16.0 equiv of
Me2S. c Typical conditions with the exception that PhMgCl was added to
CuCl, -42 to -30 °C, 1 h (∼75% conversion to 5a/7). d Yields refer to
isolated (silica gel), purified product. e dr >19:1, minor diastereomers could
Table 3. Stereochemical Invertive â-Lactone Cleavage of
[4.2.0] Bicyclics Employing Alkyl and Aryl Cuprates
1
not be detected in crude reaction mixtures (500 MHz H NMR)
33% yield over 2 steps (Table 2, entry 2). However, addi-
tional equivalents of cuprate did not increase the yield further,
likely due to the poor solubility of phenyl cuprate in THF
and the competitive reaction leading to bromide 7. Ap-
plying a Gilman-type cuprate13 by using either freshly
purified CuI or a soluble CuI source10d was not beneficial,
nor was the use of higher order cuprate reagents (Table 2,
entries 4-6).14 However, switching to the chloro Grignard
improved the yield of the desired product significantly to
72% over 2 steps (Table 2, entry 7). This counterion effect
suggested that the generation of bromide 7 was due to a
competing reaction with MgXBr, generated during cuprate
formation (X ) Br or Cl, dependent on whether PhMgBr or
PhMgCl was used, respectively). A lower concentration of
bromide ion employing PhMgCl would then account for the
improved yield of desired â-phenyl-substituted acid 5a as
noted previously by Vederas.6g Logically, we next studied
CuCl and were pleased to find that this exclusively provided
acid 5a as expected; however, conversion is lower compared
to use of CuBr‚DMS under otherwise similar conditions
(Table 2, entry 8).
a Conditions: RMgX (6.0 equiv) was added to CuBr‚DMS (3.0 equiv),
TMSCl (1.5 equiv), -42 to -30 °C, 30 min. b PhMgCl was added to CuCl,
-42 to -20 °C, 30 min. c Yields refer to isolated (silica gel), purified
product. d dr >19:1, minor diastereomers could not be detected in crude
1
reaction mixtures (500 MHz H NMR).
the intermediate carboxylic acids 10b,c were directly reduced
without purification to give the corresponding alcohols (+)-
11b and (+)-11c, respectively.
Finally, we set out to demonstrate the utility of this
methodology by targeting a Merck investigational new drug
(IND) intermediate (+)-12.15 Stereochemical invertive â-lac-
tone opening of dioxolane â-lactone (+)-1 with a fluoro-
substituted aryl cuprate would provide an expedient strategy
to ketone (+)-12, which has been used as a key intermediate
for the synthesis of anti-HIV CCR5 antagonists (Scheme 4).16
A control reaction between bicyclic â-lactone (+)-1 and
CuBr‚DMS in the absence of Grignard reagent was per-
formed and, as expected, there was no reaction. On the other
hand, a control reaction with MgBr2‚OEt2 demonstrated the
facility of the process leading to ring cleavage at 10 °C,
(12) For the earliest report of magnesium halide opening of â-lactones,
see: Gresham, T. L.; Jansen, J. E.; Shaver, F. W.; Bankert, R. A. J. Am.
Chem. Soc. 1949, 71, 2807.
(13) Gilman, H.; Jones, R. G.; Woods, L. A. J. Org. Chem. 1952, 17, 1630.
(14) Bertz, S. H.; Dabbagh, G. J. Chem. Soc., Chem. Commun. 1982,
1030.
(15) Palucki, M.; Um, J. M.; Yasuda, N.; Conlon, D. A.; Tsay, F. R.;
Hartner, F. W.; Hsiao, Y.; Marcune, B.; Karady, S.; Hughes, D. L.; Dormer,
P. G.; Reider, P. J. J. Org. Chem. 2002, 67, 5508.
(16) Conlon, D. A.; Jensen, M. S.; Plaucki, M.; Yasuda, N.; Um, J. M.;
Yang, C.; Hartner, F. W.; Tsay, F.-R.; Hsiao, Y.; Pye, P.; Rivera, N. R.;
Hughes, D. L. Chirality 2005, 17, S149.
Org. Lett., Vol. 9, No. 11, 2007
2113

studied an electron-rich aromatic Grignard reagent, m-OMe-
PhMgCl. Interestingly, this gave arylated adduct (+)-13c in
comparable yield and the 1,2-acyl adduct was again not
observed (Table 4, entries 3 and 4).
Scheme 4. Strategy toward the Merck IND Intermediate
(+)-12 via Aryl Cuprate Addition to (+)-1
To complete the synthesis of the Merck IND intermediate
(+)-12, the dioxolane group of alcohol (+)-13b was cleaved
under acidic conditions to provide the target molecule in
excellent yield, which correlated with the reported data15,16
and confirms the stereochemical outcome of the cuprate
addition (Scheme 5). Overall, the synthesis of ketone (+)-
To synthesize ketone (+)-12, a reproducible method for
preparing m-F-PhMgCl was required. After extensive screen-
ing of a variety of conditions,17 it was found that use of
entrained magnesium was most efficient for generating this
challenging Grignard reagent. Addition of this Grignard
under normal conditions led to invertive â-lactone opening
to generate a mixture of acid 5b and bromoacid 7 in a ratio
of 1.3:1 (Table 4, entry 1). To simplify the purification
Scheme 5. Overall Synthesis of Merck IND Intermediate
(+)-12 by â-Lactone Cleavage with an Aryl Cuprate
Table 4. Stereochemical Invertive Ring Cleavage of
â-Lactone-Containing [3.2.0] Bicyclics with Aryl Cuprates
12 proceeds in 6 steps from commercially available dioxolane
15 and the asymmetry is introduced through an organocata-
lytic reaction via the NCAL process.3c
In summary, stereochemical invertive, alkyl C-O cleavage
reactions of both cyclopentyl- and cyclohexyl-fused â-lac-
tones with cuprates provide access to trans-substituted cyclo-
pentanones and cyclohexanones. The overall sequence of
bicyclic â-lactone formation and cuprate addition with inver-
sion of stereochemistry complements recent catalytic, asym-
metric Michael additions.20 Normant-type cuprates gave good
yields with alkyl Grignards; however, different conditions
were developed for efficient use of aryl cuprates. Namely,
aryl cuprates required the use of chloro Grignards with CuCl
to avoid a competing bromide alkyl C-O ring cleavage. The
importance of MgXBr concentration during cuprate addition
was verified and could be minimized by use of nearly
“bromide-free” aryl cuprates derived from PhMgCl and
CuCl. This method was successfully applied to a short
synthesis of the reported Merck IND intermediate (+)-12
useful for the synthesis of anti-HIV CCR5 antagonists.
entry
Ar
CuX
% yield 13c,d
% yield 14
1a
2b
3a
4b
m-F-Ph
m-F-Ph
m-OMe-Ph
m-OMe-Ph
CuBr‚DMS
CuCl
CuBr‚DMS
CuCl
(+)-13b: 52
(+)-13b: 64
(+)-13c: 45
(+)-13c: 52
40
22
32
11
a Conditions: ArMgCl (6.0 equiv) was added to CuBr‚DMS (3.0 equiv),
TMSCl (1.5 equiv), -42 to -30 °C, 30 min. b ArMgCl was added to CuCl,
-42 to -15 °C, 1 h. c Yields refer to isolated (silica gel), purified product.
d dr >19:1, minor diastereomers could not be detected in crude reaction
1
mixtures (500 MHz H NMR).
process, this mixture was subjected to a BH3‚THF reduction
to provide a mixture of alcohols (+)-13b and 14. The two
products can be easily separated to give the desired alcohol
(+)-13b in 52% yield over two steps. Although use of CuCl
did not completely inhibit the competing bromide cleavage
due to a required catalytic amount of 1,2-dibromoethane
being used as an entrainer in forming m-F-PhMgCl,18 it did
significantly improve the ratio between desired product 5b
and the bromide 7 (Table 4, entry 2). However, a minor
amount of 1,2-addition product was observed (<5%) indicat-
ing incomplete cuprate formation due to the lower reactivity
of CuCl compared to CuBr‚DMS.19 In addition, we also
Acknowledgment. We thank the NSF (CHE-0416260)
and the Welch Foundation (A-1280) for supporting this work.
Supporting Information Available: General procedures
with characterization data (including 1H and 13C NMR
spectra) for (+)-2a, (+)-2b, (+)-2c, (+)-2d, (+)-3, (-)-4,
(+)-6a, (+)-8, (+)-10a, (+)-11b, (+)-11c, (+)-12, (+)-13b,
and (+)-13c. This material is available free of charge via
the Internet at http://pubs.acs.org.
(17) For a review describing Grignard reagents that are difficult to
generate with chemically activated magnesium, see: Lai, Y. Synthesis 1981,
585.
(18) Employing <0.1 equiv of 1,2-dibromoethane to further minimize
MgXBr concentration led to lower conversion to the Grignard reagent.
(19) Bertz, S. H.; Gibson, C. P.; Dabbagh, G. Tetrahedron Lett. 1987,
28, 4251.
OL070572P
(20) For some recent examples, see: (a) Degrado, S. J.; Mizutani, H.;
Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 13362. (b) King, H. D.;
Meng, Z.; Denhart, D.; Mattson, R.; Kumura, R.; Wu, D.; Gao, Q.; Macor,
J. E. Org. Lett. 2005, 7, 3437.
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