Enantioselective synthesis of spiropentanes from hydroxymethylallenes.

Article abstract of DOI:10.1021/ol0165140

[reaction: see text]. Hydroxymethylallenes are efficiently converted to the corresponding spiropentanes in high yields and enantiomeric ratios upon treatment with Zn(CH2I)2 and dioxaborolane ligand 1. The reaction also proceeds with complete diastereocont

Full text of DOI:10.1021/ol0165140

ORGANIC
LETTERS
2001
Vol. 3, No. 21
3293-3295
Enantioselective Synthesis of
Spiropentanes from
Hydroxymethylallenes
Andre´ B. Charette,* Eric Jolicoeur, and Gregory A. S. Bydlinski
De´partement de Chimie, UniVersite´ de Montre´al, P.O. 6128 Station Downtown,
Montre´al, Que´bec, Canada H3C 3J7
andre.charette@umontreal.ca
Received July 27, 2001
ABSTRACT
Hydroxymethylallenes are efficiently converted to the corresponding spiropentanes in high yields and enantiomeric ratios upon treatment with
Zn(CH I)2 and dioxaborolane ligand 1. The reaction also proceeds with complete diastereocontrol. The application of this methodology to the
2
synthesis of spiropentaneacetic acid is also presented.
Spiropentanes, the simplest class of spirocyclic compounds,1
have been the subject of numerous investigations to delineate
their stability, optical properties2 and overall reactivity toward
ring opening processes due to their inherent ring strain.
Recently, interest in the synthesis of such compounds has
increased due to the recognition that one of the simplest
members of this family displays interesting biological
activity. Spiropentaneacetic acid (SPA) is a medium chain
acyl-CoA dehydrogenase (MCAD) inhibitor that does not
affect amino acid metabolism.3 Both enantiomers could
effectively inactivate MCAD. Conversely, (R)-SPA-CoA is
an irreversible inhibitor of short chain acyl-CoA dehydro-
genase (SCAD) while (S)-SPA-CoA is a competitive inhibi-
tor.4 Our interest in generating spiropentane-based pharma-
cophores led us to develop an efficient diastereo- and
enantioselective method for their generation that would allow
the synthesis of substituted spiropentanemethanol derivatives.
Precedents in the literature include formation of achiral
spiropentanes,5 nonstereoselective reactions6 and reactions
that exhibit modest diastereoselectivity.7 In one case, a highly
diastereoselective reaction leading to a racemic spiropentane
(4) Li, D.; Zhou, H.-Q.; Dakoji, S.; Shin, I.; Oh, E.; Liu, H.-W. J. Am.
Chem. Soc. 1998, 120, 2008
(1) For review on oligospirocyclopropanes, see: de Meijere, A.; Kozhush-
kov, S. I. Chem. ReV. 2000, 100, 93.
(5) (a) Fitjer, L.; Conia, J.-M. Angew. Chem., Int. Ed. Engl. 1973, 12,
761. (b) Dolbier, W. R., Jr.; Akiba, K.; Riemann, J. M.; Harmon, C. A.;
Bertrand, M.; Bezaguet, A.; Santelli, M. J. Am. Chem. Soc. 1971, 93, 3933.
(f) Arora, S.; Binger, P. Synthesis 1974, 801.
(6) (a) Guan, H.-P.; Ksebati, M. B.; Cheng, Y.-C.; Drach, J. C.; Kern,
E. R.; Zemlicka, J. J. Org. Chem. 2000, 65, 1280. (b) Russo, J. M.; Price,
W. A. J. Org. Chem. 1993, 58, 3589. (c) Zefirov, N. S.; Kozhushkov, S. I.;
Ugrak, B. I.; Lukin, K. A.; Kokoreva, O. b V.; Yufit, D. S.; Struchkov, Y.
T.; Zoellner, S.; Boese, R.; de Meijere, A. J. Org. Chem. 1992, 57, 701.
(d) Erden, I. Synth. Commun. 1986, 16, 117. (e) Ullman, E. F.; Fanshawe,
W. J. J. Am. Chem. Soc. 1961, 83, 2379.
(2) For selected references, see: (a) de Meijere, A.; Khlebnikov, A. E.;
Kostikov, R. R.; Kozhushkov, S. I.; Schreiner, P. R.; Wittkopp, A.; Yufit,
D. S. Angew. Chem., Int. Ed. 1999, 38, 3474. (a) Lohr, S.; de Meijere, A.
Synlett 2001, 489. (b) Kozhushkov, S. I.; Kostikov, R. R.; Molchanov, A.
P.; Boese, R.; Benetbuchholz, J.; Schreiner, P. R.; Rinderspacher, C.;
Ghiviriga, I.; de Meijere, A. Angew. Chem., Int. Ed. 2001, 40, 180-183.
(c) Miyazawa, K.; Yufit, D. S.; Howard, J. A. K.; de Meijere, A. Eur J.
Org. Chem. 2000, 4109.
(3) Tserng, K. Y.; Jin, S.-J.; Hoppel, C. L. Biochemistry 1991, 30, 10755.
10.1021/ol0165140 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/21/2001

derivative was developed.8 Herein, we report that the chiral
dioxaborolane ligand 1 is an effective chirality controller for
the enantioselective zinc-mediated cyclopropanation of hy-
droxymethylallenes to form enantioenriched spiropentanes.
We have previously shown ligand 1 to be an effective chiral
additive for the enantioselective cyclopropanation of alco-
hols.9 We rationalized that if a similar degree of enantiofacial
selectivity and chemoselectivity is observed in the delivery
of the methylene unit at the allylic position of an allene,
then the second methylene unit could be delivered through
an alkyoxy-directed cyclopropanation that should lead to a
major diastereomer (Scheme 1).10 This strategy should also
Table 1. Formation of Spiropentanesa
Scheme 1
allow the elaboration of both stereogenic centers of a
trisubstituted spiropentane framework in a single-pot reaction
with a high degree of enantio- and diastereocontrol using
only 1 equiv of the chiral additive. However, since most
allenic alcohols are less hindered than the corresponding
trisubstituted allylic alcohols, it is not clear whether the chiral
dioxaborolane 1 will be an effective chiral controller for these
reactions.
a Unless otherwise noted, the general procedure was used with ligand
1a and the ee’s were determined by GC on chiral stationary phases. b4
c
equiv of bis(iodomethyl)zinc‚DME complex were required. Determined
d
by 13C NMR from amide derivative. Ligand 1b was used. eSubstrate was
f
submitted to reaction conditions twice. Determined by 19F NMR of its
Mosher ester derivative. gDetermined by HPLC on chiral stationary phases.
For our initial studies we have chosen achiral hydroxy-
methylallenes to facilitate analysis of the spiropentane
products. The hydroxymethylallenes are readily available
from the parent ketones according to a four-step protocol
described in the literature.11 The desired spiropentanes were
obtained by the addition of dioxaborolane 1a and hydroxy-
methylallene to the Zn(CH2I)2‚DME complex. In most cases,
conversion to the spiropentane proceeded in high yields and
only one diastereomer was observed by 1H NMR (Table 1).12
Terminal hydroxymethylallene 2 provides the desired
spiropentane with fair yield and good ee. Primary alkyl
substrates whether acyclic (3, 4) or cyclic (5, 6) react to give
good yields of the corresponding spiropentanes with excellent
ee (g92%). In the case of substrates bearing secondary alkyl
substituents (such as 7), a second treatment with bis-
(iodomethyl)zinc reagent was required to obtain an accept-
able yield and high ee of the desired spiropentane.13 In
contrast, the sterically hindered but rigid adamantyl derivative
8 reacted in excellent yield and selectivity to give the desired
spiropentane 17. Highly hindered 9 provided exclusively the
methylenecyclopropane 18 with excellent enantiocontrol.
Diphenylhydroxymethylallene 10 proved to be a sluggish
substrate giving only a poor yield of spiropentane 19;
(7) (a) Trost, B. M.; Bogdanowicz, M. J. J. Am. Chem. Soc. 1973, 95,
5307. (b) Maurin, M.; Bertrand, M. Bull. Soc. Chim. Fr. 1970, 2261. (c)
Bertrand, M.; Maurin, R. Bull. Soc. Chim. Fr. 1967, 2779.
(8) (a) Wiberg, K. B.; Snoonian, J. R. J. Org. Chem. 1998, 63, 1390.
(b) Wiberg, K. B.; Snoonian, J. R. J. Org. Chem. 1998, 63, 1402.
(9) (a) Charette, A. B.; Juteau, H. J. Am. Chem. Soc. 1994, 116, 2651.
(b) Charette, A. B.; Lebel, H.; Molinaro, C. J. Am. Chem. Soc. 1998, 120,
11943. (c) Charette, A. B.; Prescott, S.; Brochu, C. J. Org. Chem. 1995,
60, 1081.
(10) (a) Mohr, P. Tetrahedron Lett. 1995, 36, 7221. (b) For a compre-
hensive review of substrate-directable reactions, see: Hoveyda, A. H.; Evans
D. A.; Fu G. C. Chem. ReV. 1993, 93, 1307.
(11) Cowie, J. S.; Landor, P. D.; Landor, S. J. J. Chem. Soc., Perkin
Trans. 1 1973, 720.
(12) The absolute stereochemistry has been established only in the case
of entry 7 for which an X-ray crystal structure of the (S)-Mosher ester
derivative has been obtained (see Supporting Information for details).
(13) When reaction was stopped after the addition of only one treatment
of zinc reagent. A lower yield and ee was observed (25% yield, 83% ee).
3294
Org. Lett., Vol. 3, No. 21, 2001

however, the enantiomeric excess was excellent. From these
results, it is clear that the chiral controller is quite effective
for the enantioselective cyclopropanation of hydroxymethyl-
allenes. To determine the site of the first cyclopropanation,
the reaction was carefully monitored by GC and the initial
product formation was compared to authentic alkylidene-
cyclopropylmethanol derivatives of substrate 3 to 10.14 GC
analysis of the bis(cyclopropanation) reaction as a function
of time unambiguously showed that the allylic position is
the first site that is cyclopropanated. However, attempts to
cyclopropanate the allylic position exclusively were unsuc-
cessful. As noted by Lautens,15 this observation probably
could be a consequence of the higher reactivity of the
vinylcyclopropane intermediate compared to the allenic
alkoxide.
in the presence of both antipodes of the chiral additive,
significantly different diastereoselectivities were observed
(entry 3, 4). The matched pair involving (-)-20 and (S,S)-
1a led to an excellent diastereoselectivity (entry 4) whereas
the mismatched case led to an slight reversal of diastereo-
selectivity (entry 3). These observations are consistent with
the transition structure that has been proposed for the
cyclopropanation reaction involving ligand 1a.
The methodology was then applied to the synthesis of (+)-
SPA. The synthetic route (Scheme 2) allows access to
Scheme 2a
A preliminary investigation into the bis(cyclopropanation)
of chiral allene 20 was then carried out to see if double
stereodifferentiation was possible (Table 2). When allene
a (a) DME, Et2Zn, CH2I2, 1a, CH2Cl2, -10 °C to room temper-
ature, 69%; (b) MsCl, Et3N, CH2Cl2, 0 °C; 2. NaCN, DMSO, sealed
tube, rt; 3. add HCl concentrated, 100 °C, 34%.
Table 2. Formation of Spiropentanes from Chiral Substratea
numerous optically enriched analogues of SPA.19 Spiropen-
tane 11, obtained in 86% ee after the cyclopropanation, was
then mesylated (MsCl, Et3N, CH2Cl2), and the mesylate was
immediately treated with NaCN followed by nitrile hydroly-
sis to give enantioenriched (+)-SPA 24 in an overall yield
of 23% from starting allene (2).
In summary, the present work provides the first enanti-
oselective method to prepare chiral, nonracemic spiropen-
tanes from achiral hydroxymethylallenes in high yield and
excellent ee. Preliminary investigations of the diastereo-
selectivity of the ligand-assisted reaction with chiral hy-
droxymethylallenes demonstrates the possibility for matched
and mismatched ligand/substrate pairs. Further studies on
the diastereoselective cyclopropanation of chiral, nonracemic,
hydroxymethylallenes along with the use of substituted
spiropentane derivatives as pharmacophores will be reported
in due course.
a General procedure was used, presence and ytpe of ligand is specified.
b(()-20 with no ligand. c(()-20 with ligand (R,R)-1b. d(()-20 with ligand
e
(R,R)-1a. (-)-20 substrate with ligand (S,S)-1a.
Acknowledgment. This work was supported by NSERC
(Canada), DowAgrosciences, and the Universite´ de Montre´al.
We also acknowledge Dr. Tan Phan Viet, Carl Berthelette,
Sylvie Bilodeau, and Francine Be´langer-Garie´py for their
technical support.
(()-20 was subjected to a ligand-free cyclopropanation
reaction, two separable diastereomeric products 21 and 22
were formed in a 89:11 ratio (entry 1).15,16 When allene (()-
20 was subjected to the bis(cyclopropanation) conditions
using dioxaborolane (R,R)-1a, the major product (21) was
formed in only 12% de indicating that no kinetic resolution
was possible in these reactions (entry 2).17 Conversely, when
chiral, nonracemic (-)-2018 was treated with the zinc reagent
Supporting Information Available: Experimental pro-
cedures, X-ray crystallographic orteps, characterization data,
and spectra (1H and 13C NMR) for the new compounds are
available. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) Lautens, M.; Delanghe, P. H. M. J. Am. Chem. Soc. 1994, 116,
8526.
(15) The relative stereochemistry of the two diastereomeric spiropentanes
was determined by NOESY of the corresponding p-nitrobenzoate ester
derivative 23.
OL0165140
(16) Unoptimized yield.
(18) (-)-28 was prepared according to Myers’s procedure: Myers, A.
G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492.
(19) Application of the methodology to a homoallenic alcohol (3,4-
butadiene-1-ol) provided the desired spiropentane with only 47% ee.
(17) As observed previously, both enantiomers react at similar rates under
the reaction conditions. For a related study using chiral allylic alcohols,
see: Charette, A. B.; Lebel, H.; Gagnon, A. Tetrahedron 1999, 55, 8845.
Org. Lett., Vol. 3, No. 21, 2001
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