Formal enantioselective synthesis of (+)-compactin

Article abstract of DOI:10.1021/ol0527328

The challenging structural features and important biological activity of (+)-compactin (1) explain the substantial synthetic interest that it has generated. We report a novel enantioselective approach to the advanced intermediate 2a, which constitutes a formal synthesis of (+)-1. The sequence utilizes MacMillan's organocatalytic Mukaiyama-Michael reaction, which stereoselectively adds the silyloxyfuran 6 to α,β-unsaturated aldehyde 7. The chirality generated in this reaction guides the formation of the other three consecutive stereocenters found in 2a.

Full text of DOI:10.1021/ol0527328

ORGANIC
LETTERS
2006
Vol. 8, No. 4
597-600
Formal Enantioselective Synthesis of
)-Compactin
(+
Joe1l Robichaud* and Franc¸ois Tremblay
Merck Frosst Canada Ltd., 16711 Trans Canada Highway,
Kirkland, Que´bec H9H 3L1, Canada
joel_robichaud@merck.com
Received November 10, 2005
ABSTRACT
The challenging structural features and important biological activity of (
generated. We report a novel enantioselective approach to the advanced intermediate 2a, which constitutes a formal synthesis of (
+
)-compactin (1) explain the substantial synthetic interest that it has
)-1. The
-unsaturated
aldehyde 7. The chirality generated in this reaction guides the formation of the other three consecutive stereocenters found in 2a.
+
sequence utilizes MacMillan’s organocatalytic Mukaiyama Michael reaction, which stereoselectively adds the silyloxyfuran 6 to
−
r,â
The discovery of (+)-compactin1 (1) and its ability to inhibit
the hydroxymethylglutaryl coenzyme A (HMG-CoA) reduc-
tase, which has a key role in endogeneous cholesterol
biosynthesis, has led to the publication of several syntheses2
and the development of a therapeutic class of compounds
(i.e., statins) that are currently used as cholesterol-lowering
drugs.
While many diverse strategies to (+)-compactin (1) have
been devised, several of these approaches are similar in their
interception at closely related advanced intermediates 2a-d
(see Figure 1). These compounds all bear the completed
(1) (a) Endo, A.; Kuroda, M.; Tsujita, Y. J. Antibiot. 1976, 29, 1346.
(b) Endo, A.; Kuroda, M.; Tanzawa, K. FEBS Lett. 1976, 72, 323. (c) Endo,
A.; Tsujita, Y.; Kuroda, M.; Tanzawa, K. Eur. J. Biochem. 1977, 77, 31.
(d) Brown, A. G.; Smale, T. C.; King, T. J.; Hasenkamp, R.; Thompson,
R. H. J. Chem. Soc., Perkin Trans. I 1976, 1165.
(2) (a) Wang, N. Y.; Hsu, C. T.; Sih, C. J. J. Am. Chem. Soc. 1981, 103,
6538. (b) Hirama, M.; Uei, M. J. Am. Chem. Soc. 1982, 104, 4251. (c)
Girotra, N. N.; Wendler, N. L. Tetrahedron Lett. 1982, 23, 5501, (d) Girotra,
N. N.; Wendler, N. L. Tetrahedron Lett. 1983, 24, 3687. (e) Grieco, P. A.;
Zelle, R. E.; Lis, R.; Finn, J. J. Am. Chem. Soc. 1983, 105, 1403. (f)
Anderson, P. C.; Clive, D. L. J.; Evans, C. F. Tetrahedron Lett. 1983, 24,
1373. (g) Rosen, T.; Taschner, M. J.; Thomas, J. A., Heathcock, C. H. J.
Org. Chem. 1985, 50, 1190. (h) Heathcock, C. H.; Hadley, C. R.; Rosen,
T.; Theisen, P. D.; Hecker, S. J. J. Med. Chem. 1987, 30, 1858. (i) Keck,
G. E.; Kachensky, D. F. J. Org. Chem. 1986, 51, 2487. (j) Kozikowski, A.
P.; Li, C.-S. J. Org. Chem. 1987, 52, 3541. (k) Clive, D. L. J.; Murthy, K.
S. K.; Wee, A. G. H.; Prasad, J. S.; da Silva, G. V. J.; Majewski, M.;
Anderson, P. C.; Haugen, R. D.; Heerze, L. D. J. Am. Chem. Soc. 1988,
110, 6914. (l) Danishefsky, S. J.; Simoneau, B. J. Am. Chem. Soc. 1989,
111, 2599. (m) Daniewski, A. R.; Uskokovic, M. R. Tetrahedron Lett. 1990,
31, 5599, (n) Daniewski, A. R.; Uskokovic, M. R. Bull. Soc. Chim. Fr.
1990, 127, 849. (o) Burke, S. D.; Deaton, D. N. Tetrahedron Lett. 1991,
32, 4651. (p) Hung, S.-H.; Liao, C.-C. J. Chem. Soc., Chem. Commun.
1993, 1457. (q) Hagiwara, H.; Nakano, T.; Kon-no, M.; Uda, H. J. Chem.
Soc., Perkin Trans. 1 1995, 777.
Figure 1. Key advanced intermediates to (+)-compactin.
decalin core along with its four contiguous chiral centers.
The only remaining synthetic efforts involve the sequential
elaboration of both alcohol moieties of 2a-d to the desired
chiral (S)-2-methylbutyric ester side chain and the â-hydroxy
lactone appendage present in 1.
Our novel synthetic strategy (see Figure 2) targets the
advanced intermediate diol 2a by a sequence showcasing
four key reactions which allow the construction of both
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Scheme 1. Enantioselective Mukaiyama-Michael addition
Figure 2. Retrosynthetic analysis of diol 2a.
cyclohexene rings of 1 in an efficient and elegant manner.
Furthermore, the devised route will allow all of the chirality
of 2a to be derived from a single stereocenter that is created
very early in the synthetic scheme.
The first disconnection of our retrosynthetic analysis of
diol 2a involves a ring-closing metathesis (RCM) reaction
of the triene portion of 3 to form the completed decalin core
of 1. Our second key disconnection requires a diastereose-
lective conjugate addition of a vinylcopper reagent onto the
less hindered top face (re face) of the exocyclic (Z)-R,â-
unsaturated lactone 4, thereby creating the last two of the
four requisite stereocenters of 2a.
Construction of the bicyclic lactone 4 is envisaged via a
diastereoselective intramolecular cyclization of the gem-
dibromoalkene 5 onto the R,â-unsaturated lactone moiety.
Finally, the chiral R,â-unsaturated lactone 5 would be
accessible via the enantioselective Mukaiyama-Michael
addition of a trimethylsilylfuran unit (6) onto aldehyde 7 by
exploiting MacMillan’s recently reported organocatalytic
technology.3 Thus the chirality generated in this first key
step would guide the formation of all subsequent chiral
centers present in diol 2a.
aldehyde 7a was prepared from propargyl alcohol 8 accord-
ing to a two-step literature procedure5 to afford the trans-
substituted allylic alcohol 9a which was oxidized with MnO2
to afford aldehyde 7a. The BDMS-substituted aldehyde 7b
was also prepared from propargyl alcohol 8 by direct
hydrosilylation6 with benzyldimethylsilane to afford the
trans-allylic alcohol 9b, which was also oxidized with MnO2
to the corresponding aldehyde 7b.
Mukaiyama-Michael addition of the silyloxyfuran unit
6 onto these aldehydes (7a and 7b) proceeded with good to
moderate enantioselectivity and excellent diastereoselectivity.
The addition product bearing the TMS moiety 11a was
obtained in 95% yield with an enantioselectivity of 82% ee
and excellent diastereoselectivity (>30:1 syn/anti ratio). The
BDMS-substituted product 11b was obtained in 60% yield
with an enantioselectivity of 70% ee and excellent diaste-
reoselectivity (>30:1 syn/anti ratio).7 Subsequent conversion
of the aldehyde functionality in 11a and 11b to the
corresponding gem-dibromide 5a and 5b (see Scheme 2) was
accomplished using the Corey-Fuchs procedure.8
The next key reaction of our sequence required the
diastereoselective construction of the first cyclohexene ring
of diol 2a. After probing without success various methods
such as the reductive Heck-type coupling and the intramo-
lecular Michael addition of in situ generated organometallic
species, it was discovered that the desired intramolecular
cyclization could be accomplished under radical conditions.
Treatment of gem-dibromides 5a and 5b with tributyltin
hydride and AIBN in refluxing ethyl acetate afforded the
desired cis-fused bicyclic lactones 12a and 12b via diaste-
reoselective cyclization along with an equivalent amount of
the reduced vinylic bromides 13a and 13b,9 which were
easily separated by flash chromatography. The stereochem-
Based on MacMillan’s results,3 we expected that substit-
uents equal to or larger than a methyl in the â position of
aldehyde 7 should furnish good levels of stereoselectivity.
Not surprisingly, the lack of any subsituent (R ) H, data
not shown) led to a very poor enantioselectivity of 33% ee.
While the replacement of that â hydrogen with halogens
failed to afford any Mukaiyama-Michael addition products,
incorporation of other bulkier substituents (R ) StBu, SPh,
data not shown) provided the desired addition products albeit
with low diastereoselectivity (∼3:1).
These results led us to hypothesize that the â substituent
of aldehyde 7 requires steric bulk at least equiValent to that
of an isopropyl group4 in order to achieve good stereose-
lectivity. As a result, both the trimethylsilyl- (7a, R ) TMS)
and benzyldimethylsilyl-substituted (7b, R ) BDMS) alde-
hydes were prepared (see Scheme 1). The TMS-substituted
(5) Denmark, S. E.; Jones, T. K. J. Org. Chem. 1982, 47, 4597.
(6) Takeuchi, R.; Nitta, S.; Watanabe, D. J. Org. Chem. 1995, 60, 3045.
(7) Because of the instability of aldehydes 11a and 11b, the measurement
of enantioselectivity (by chiral HPLC) was conducted at the dibromide stage
(5a and 5b).
(3) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2003, 125, 1192.
(4) A personal communication from MacMillan at this stage informed
us that an error had occurred in the production of the manuscript that resulted
in a methyl substituent being shown where an isopropyl group was intended.
This typographical error is resolved in the Supporting Information wherein
the correct isopropyl-substituted substrate is described.
(8) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769.
(9) Obtainment of a statistical mixture of cyclized and reduced products
has been reported on an analogous system: Nishida, M.; Hayashi, H.;
Yamaura, Y.; Yanaginuma, E.; Yonemitsu, O.; Nishida, A.; Kawahara, N.
Tetrahedron Lett. 1995, 36, 269.
598
Org. Lett., Vol. 8, No. 4, 2006

Scheme 2. Diastereoselective cyclisation
Scheme 3. Diastereoselective conjugate addition
Michael addition15 of a vinyl copper reagent onto the less
hindered top face (re face) of the exocyclic (Z)-R,â-
unsaturated lactones 4a and 4b afforded the desired lactones
3a and 3b16 with diastereoselectivities of 6.4:1 and 6.7:1,
respectively. The relative stereochemistry of the chiral center
R to the lactone (3b) was confirmed by NMR as a large
NOE was observed between the allylic methine of the side
chain with the proximal angular proton. This key reaction
completes the creation of the third and fourth consecutive
chiral centers of diol 2a.
istry of the bicyclic cis-junction was confirmed by NMR
which showed a large NOE between the two angular protons
of 12a.
Subsequent Stille cross-coupling of the remaining vinylic
bromide functionality of 12a and 12b with vinyltributyltin
afforded the desired dienes 14a and 14b. It should be noted
that all desilylation10 attempts with either bromides 12a and
12b or dienes 13a and 13b resulted in the opening of the
lactone moiety via elimination of the silicon group.11
Attempts to circumvent this problem by first opening or
reducing the lactones to the corresponding hydroxy acids/
esters or diols (data not shown) also failed to afford the
desired desilylation products and yielded other undesired
compounds that have not been fully characterized. In view
of these difficulties, the removal of the silicon group was
postponed until a later stage in the synthetic sequence.
We then set out to install the two remaining chiral centers
of the compactin core. It was predicted that the steric
hindrance caused by the vinylic moiety of 15a and 15b would
force the methyl substituent of the exocyclic R,â-unsaturated
double bond to adopt the (Z)-configuration.12 The obtainment
of this (Z)-geometry is critical as the Michael addition onto
the trans isomer would produce the undesired diastereoiso-
mer.
LAH reduction (see Scheme 4)of lactones 3a and 3b
provided the diols 16a and 16b which set the stage for the
Scheme 4. Ring closing metathesis
Toward this end, lactones 14a and 14b were phosphory-
lated13 (see Scheme 3) to afford phosphonates 15a and 15b
and then treated with sodium hydride and acetaldehyde14 to
provide the desired (Z)-exo-R,â-unsaturated lactones 4a and
4b. The stereochemistry of the double bond of 4a was
confirmed by NMR analysis which showed a large NOE
between the vinylic proton of the (Z)-exo-R,â-unsaturated
lactone with the proximal angular proton.
contruction of the decalin core of 2a. Treatment of trienes
16a and 16b with Grubb’s second generation catalyst
smoothly accomplished ring closing metathesis17 to afford
(10) (a) Micalizio, G. C.; Roush, W. R. Org. Lett. 2000, 2, 461. (b)
Micalizio, G. C.; Roush, W. R. Org. Lett. 2001, 3, 1949. (c) Hudrlik, P. F.;
Hudrlik, A. M.; Kulkarni, A. K. J. Am. Chem. Soc. 1982, 104, 6809. (d)
Hudrlik, P. F.; Holmes, P. E.; Hudrlik, A. M. Tetrahedron Lett. 1988, 29,
6395.
(11) This type of reaction has been reported: (a) Daly, M. J.; Ward, R.
A.; Thompson, D. F.; Procter, G. Tetrahedron Lett. 1995, 36, 7545. (b)
Russell, A. T.; Procter, G. Tetrahedron Lett. 1987, 28, 2041.
(12) Amber, W.; Seebach, D. Chem. Ber. 1990, 123, 2413.
(13) Du, Y.; Wiemer, D. F. J. Org. Chem. 2002, 67, 5701.
(14) Janecki, T.; Blaszczyk, E. Synthesis 2001, 403.
(15) (a) Steurer, S.; Podlech, J. Eur. J. Org. Chem. 2002, 899. (b)
Bennabi, S.; Narkunan, K.; Rousset, L.; Bouchu, D.; Ciufolini, M. A.
Tetrahedron Lett. 2000, 41, 8873. (c) Sahlber, C. Tetrahedron Lett. 1992,
33, 679.
(16) In one experiment we obtained a mixture of epimers R to the lactone
which were equilibrated to the desired trans epimer using t-BuOK in t-BuOH
at rt for 15 min.
(17) Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310.
Org. Lett., Vol. 8, No. 4, 2006
599

17a and 17b.18 The only remaining chemical transformation
at this stage involved the desilylation reaction which was
carried out using TBAF and potassium tert-butoxide in a
DMSO-water mixture.10 This desilylation provided the
targeted (+)-compactin diol 2a in 31% from the TMS
substituted decalin 17a and in 36% yield from the BDMS-
substituted decalin 17b. The characterization data for diol
2a proved to be identical with published information.2f
All attempts to improve the yield of the desilylation step
using other methods or by modifying the reaction conditions
failed. The reaction with the TMS-substituted decalin 16a
gave rise to a substantial amount of an aromatized product.
It was hypothesized that the BDMS-substituted compound
16b would behave differently as the benzyl group is rapidly
cleaved under the reaction conditions to afford the more
reactive silanol intermediate. While this change did avoid
the production of the aromatic side product, the yield
obtained was only moderately improved.
Our synthetic sequence constructs the four consecutive
chiral centers of the (+)-compactin diol 2a from the first
chiral center generated by MacMillan’s organocatalytic 1,4-
addition of a trimethylsilyloxyfuran unit (6) onto R,â-
unsaturated aldehydes (7a and 7b). Subsequent diastereo-
selective radical cyclization of vinyl bromides 5a and 5b
efficiently secures the formation of the first cyclohexene ring
while simultaneously generating the second chiral center.
Finally, Michael addition of a vinyl group onto the least
hindered face of the (Z)-exo-R,â-unsaturated lactones 4a and
4b not only generates the two remaining chiral centers (3a
and 3b), but also introduces the desired vinyl substituent,
poised to undergo a ring-closing metathesis to complete the
formation of the Decalin core of the (+)-compactin diol 2a.
This synthetic route was carried out with both TMS and
BDMS substituted aldehydes (9a and 9b). The appeal of the
TMS-substituted sequence centers on the higher yield and
enantioselectivity obtained for the Mukaiyama-Michael
reaction (11a), whereas the advantage of the BDMS substitu-
tion rests in that its sequence is one step shorter and that the
yield obtained for the diastereoselective Michael addition
(3b) has been significantly improved.
Our formal stereoselective approach to (+)-compactin (1)
is distinct from all published synthetic efforts2 and provides
access to diol 2a, a key synthetic intermediate in a number
of other syntheses of 1. This synthesis was conducted in a
reasonably short number of steps (12 steps for the BDMS-
substituted sequence and 13 steps for TMS-substituted
sequence) from inexpensive commercially available reagents.
Acknowledgment. We thank Sheldon Crane and Renata
Oballa for useful discussions and Laird Trimble and Dan
Sorensen for NMR analyses.
Supporting Information Available: Experimental pro-
cedures and analytical data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(18) At this stage, the minor diastereoisomer resulting from the Michael
addition of the vinyl group onto the opposite side of the (Z)-exo-R,â-
unsaturated lactones 4a and 4b was separated by flash chromatography.
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