A highly diastereoselective, tandem Mukaiyama aldol-lactonization route to β-lactones: Application to a concise synthesis of the potent pancreatic lipase inhibitor, (-)-panclicin D

Full text of DOI:10.1021/jo9619488

4
J . Org. Chem. 1997, 62, 4-5
A High ly Dia ster eoselective, Ta n d em
Mu k a iya m a Ald ol-La cton iza tion Rou te to
â-La cton es: Ap p lica tion to a Con cise
Syn th esis of th e P oten t P a n cr ea tic Lip a se
In h ibitor , (-)-P a n clicin D
Sch em e 1
Hong Woon Yang and Daniel Romo*
Department of Chemistry, Texas A&M University,
College Station, Texas 77843-3255
the recently approved antiobesity agent tetrahydrolip-
statin (Orlistat).9
Treatment of various aldehydes in a methylene chlo-
Received October 17, 1996
ride slurry of freshly fused ZnCl
available ketene thioacetal 2b gave almost exclusively
2
with the readily
â-Lactones (2-oxetanones) have recently emerged as
important synthetic targets due to their occurrence in a
variety of natural products, their utility as versatile
synthetic intermediates, and their use as monomers for
the preparation of biodegradable polymers.1 As part of
a program directed toward the asymmetric synthesis and
the development of new transformations of â-lactones,
we have been searching for general and efficient diaster-
eo- and enantioselective methods for their preparation.
In connection with these studies, we now report on an
exceptional tandem aldol-lactonization process that pro-
vides direct access to achiral and chiral 3,4-disubstituted-
â-lactones with high stereoselectivity.2 This method
builds on work recently reported by Hirai and co-workers3
and compliments the tandem aldol-lactonizations re-
cently reported by Danheiser and Schick5 employing
enolates derived from various acid derivatives. The latter
methods provide good yields of â-lactones from ketones
and some aldehydes; however, the stereoselectivity of
these reactions with aldehydes appears to be highly
dependent on the substitution of the thiol ester and
aldehyde employed. In contrast, the tandem Mukaiyama
aldol-lactonizations reported herein employing readily
the trans-R-methyl â-lactones 3a -f in moderate to good
10
yields (Table 1).
Purification of the â-lactones was
simplified in some cases by treatment of the reaction
mixture with CuBr followed by hydrolysis which re-
2
moved both unreacted ketene thioacetal and any thiol
11
ester formed during the reaction. The stereochemistry
of the â-lactones 3 was readily assigned by inspection of
the coupling constants of the C3,C4 protons of the
12
â-lactone ring (J Ha,Hb ∼ 6 Hz for cis, 4-4.5 Hz for trans).
The stereochemical outcome of these reactions is in
accord with previous reports of Mukaiyama aldol reac-
tions employing ketene thioacetals which proceed through
13
open transition states.
An exception is the reaction
with p-nitrobenzaldehyde which is the single example of
â-lactone synthesis reported by Hirai. In this case, the
methyl-substituted ketene thioacetal 2a was employed
and the cis-substituted â-lactone 3h was the only product
4
3a
isolated (23% yield). We obtained the same â-lactone
employing ketene thioacetal 2b (Table 1, entry 15), and
the cis stereochemical outcome was verified by single
14
crystal X-ray analysis.
This intriguing reversal in
stereoselectivity with p-nitrobenzaldehyde is consistent
with a recent report of TiCl -mediated aldol condensa-
6
available ketene thioacetals 2b and 2c and both racemic
4
and optically active aldehydes proceed at ambient tem-
7
tions of benzaldehyde and ketene thioacetals; however,
a rationalization of the stereochemical outcome in the
present reaction involving ZnCl must await further
2
studies. As mentioned above, the present tandem reac-
tion can also be applied to the synthesis of R-unsubsti-
tuted â-lactones 4a -g using the acetic acid derived
ketene thioacetal 2c (Table 1).
7
perature with high levels of stereocontrol (Scheme 1). In
addition, this process provides the first general route to
R-unsubstituted-â-lactones by a tandem-aldol lactoniza-
tion sequence in contrast to previous methods.5 The
utility of this method is demonstrated by a concise
8
synthesis of (-)-panclicin D, a recently isolated pancre-
atic lipase inhibitor with twice the inhibitory activity of
Some limitations of the present method were noted.
In the case of pivalaldehyde, the reaction only proceeds
when the acetal 2c is employed (cf. entries 13, 14). When
this aldol-lactonization procedure was applied to R,â-
unsaturated aldehydes and some aromatic aldehydes no
â-lactones were isolated, but instead olefinic products
derived from apparent in situ elimination of the â-lac-
*
To whom correpondence should be addressed: Tel: 409-845-9571;
Fax: 409-845-4719; E-mail: romo@chemvx.tamu.edu.
1) (a) For a recent review of â-lactone chemistry, see: Pommier,
(
A.; Pons, J .-M. Synthesis 1993, 441-449. For recent reviews of
â-lactone-containing natural products, see: (b) Lowe, C.; Vederas, J .
Org. Prep. Proced. Int. 1995, 27, 305-346. (c) Pommier, A.; Pons, J .-
M. Synthesis 1995, 729-744. (d) For a lead reference to polymers
derived from â-lactones, see: J edlinski, Z.; Kurcok, P.; Kowalczuk, M.;
Matuszowicz, A.; Dubois, P.; J erome, R.; Kricheldorf, H. R. Macromol-
ecules 1995, 28, 7276-7280.
1
5
tones were detected in the crude reaction mixtures. In
(
2) Reetz, M. T.; Schmitz, A.; Holdgrun, X. Tetrahedron Lett. 1989,
0, 5421-5424.
3) (a) Hirai, K.; Homma, H.; Mikoshiba, I. Heterocycles 1994, 38,
(8) Isolation and biological activity: (a) Yoshinari, K.; Aoki, N.;
Ohtsuka, T.; Nakayama, N.; Itezono, Y.; Mutoh, M.; Watanabe, J .;
Yokose, K. J . Antibiot. 1994, 47, 1376-1384. Structure determination:
(b) Mutoh, M.; Nakada, N.; Matsukuma, S.; Ohshima, S.; Yoshinari,
K.; Watanabe, J .; Arisawa, M. J . Antibiot. 1994, 47, 1369-1375.
(9) Zhi, J .; Melia, A. T.; Guerciolini, R.; Chung, J .; Kinberg, J .;
Hauptman, J . B.; Patel, I. H. Clin. Pharm. Ther. 1994, 56, 82.
(10) A general procedure for the tandem Mukaiyama aldol-lacton-
ization can be found in the supporting information.
(11) Kim, S.; Lee, J . I. J . Org. Chem. 1984, 49, 1712-1716.
(12) Mulzer, J .; Zippel, M.; Bruntrup, G.; Segner, J .; Finke, J . Liebigs
Ann. Chem. 1980, 1108.
(13) Gennari, C.; Beretta, M. G.; Bernardi, A.; Moro, G.; Scolastico,
C.; Todeschini, R. Tetrahedron 1986, 42, 893-909.
3
(
2
81-282. (b) For related work involving the one-step synthesis of
â-lactams, see: Annunziata, R.; Cinquini, M.; Cozzi, F.; Molteni, V.;
Schupp, O. Tetrahedron 1996, 52, 2573-2582.
(4) (a) Danheiser, R. L.; Nowick, J . S. J . Org. Chem. 1991, 56, 1176-
1
185. (b) Danheiser, R. L.; Nowick, J . S.; Lee, J . H.; Miller, R. F.;
Huboux, A. H. Org. Synth. 1995, 73, 61.
5) Wedler, C.; Kleiner, K.; Kunath, A.; Schick, H. Liebigs. Ann.
996, 881-885 and references cited.
(
1
(
6) The ketene thioacetals 2b (∼20:1 Z(O):E(O)) and 2c are readily
prepared from the corresponding acids in two steps by standard
acylation and silylation, see: Hirai, K.; Iwano, Y.; Mikoshiba, I.;
Koyama, H.; Nishi, T. Heterocycles 1994, 38, 277-280 and ref 3b.
(14) The X-ray data of â-lactone 3h has been deposited with the
Cambridge Crystallographic Data Centre. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
(7) For a recent report of the use of ketene thiopyridylacetals in aldol
reactions, see: Suh, K.-H.; Choo, D.-J . Tetrahedron Lett. 1995, 36,
109-6112.
6
S0022-3263(96)01948-2 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 1, 1997
5
Sch em e 2a
Ta ble 1. Syn th esis of Ra cem ic â-La cton es 3 a n d 4 via
Ta n d em Ald ol-La cton iza tion of Ald eh yd es a n d Keten e
Aceta ls 2b a n d 2c
selectivity should make this procedure the method of
choice for preparing various trans-3,4-disubstituted â-lac-
tones as demonstrated by the first total synthesis of (-)-
panclicin D. We are presently seeking to further optimize
this aldol-lactonization sequence, and the results of these
studies will be described in a full account of this work.
Ack n ow led gm en t. Support of this work by the NSF
in the form of a Minority Planning Grant (CHE 9510566)
and a CAREER award (CHE 9624532) to D.R. is grate-
fully acknowledged. Dr. N. Nakada and Mr. K. Yoshi-
nari from Nippon Roche (J apan) kindly provided spec-
tral data of natural (-)-panclicin D. We thank Dr. Lloyd
Sumner and Dr. Barbara Wolfe for obtaining mass
spectral analysis, and Dr. J oe Reibenspies for perform-
ing the X-ray analysis.
addition, while some aldehydes bearing pendant pro-
tected alcohols provided the desired â-lactones, others
gave products resulting from further reaction of the
presumed â-lactone intermediate.16
The utility of this methodology is demonstrated by an
extremely concise total synthesis of (-)-panclicin D. The
synthesis began with a Brown asymmetric allylation of
d
n-octanal using d-B-allyldiisopinocampheylborane ( Ipc
2
-
BAll)17 to give the homoallylic alcohol 6 in 55% yield and
1
8
9
2% ee (Scheme 2).
Alcohol protection followed by
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures including synthesis and characterization of all new
compounds reported herein; chiral GC traces of alcohol 6 and
spectral data of selected â-lactones and natural and synthetic
ozonolysis provided the aldehyde 8 in 88% yield (two
steps). Application of the tandem aldol-lactonization to
this aldehyde and ketene thioacetal 919 proceeded smoothly
(-)-panclicin D (25 pages).
to give the â-lactones 10 as a 9.3:1 mixture of diastereo-
mers. These were directly desilylated to afford the more
readily purified, hydroxy â-lactones 11, that were sepa-
rable by flash chromatography, in 53% overall yield from
aldehyde 8. As expected, the major diastereomer 11
possessed a trans-substituted â-lactone (J Ha,Hb ) 4.2 Hz),
and the relative stereochemistry was subsequently de-
termined to be anti by conversion to (-)-panclicin D.
Mitsunobu reaction employing N-formylglycine provided
synthetic (-)-panclicin D (12) which displayed spectral
J O9619488
(
15) A related process has been previously observed in Al-catalyzed
[
2 + 2] cycloadditions of ketenes and both aromatic and R,â-unsatur-
ated aldehydes: Concepcion, A. B.; Maruoka, K.; Yamamoto, H.
Tetrahedron 1995, 51, 4011-4020.
(16) A rather interesting result is observed in reaction of aldehyde
i under typical aldol-lactonization conditions. This gave the tetrahy-
1
drofuran ii as predominantly one diastereomer (>19:1, 200 MHz
H
NMR, cf. Mead, K. T.; Park, M. J . Org. Chem. 1992, 57, 2511-2514).
The relative stereochemistry has not been determined at this time but
is based on the expected, initially formed trans-â-lactone undergoing
an inversion process during intramolecular cyclization of the pendant
ether (unpublished results of M. Scott Champ).
and physical properties that matched those of the natural
product ([R]20
) -23.0 (c 0.30, CHCl
); lit. [R]
20
) -23
D
3
D
8
b
(
3
c 0.30, CHCl )). This synthesis constitutes one of the
most concise and efficient routes to this class of lipase
inhibitors (six steps, 20% overall yield from n-octanal)
and is readily adapted to prepare any member of this
family.
2
In conclusion, we have found that the ZnCl -medi-
(
17) Racherla, U. S.; Brown, H. C. J . Org. Chem. 1991, 56, 401-404.
(18) Enantiomeric excess was determined by GC analysis using a
t-BuMe Si â-cylodextrin column: Shitangkoon, A.; Vigh, G. J . Chro-
matogr. A 1996, 31-42.
19) This ketene acetal was prepared in three steps from lauric acid.
See supporting information for experimental details.
ated tandem aldol-lactonization reaction provides an
expedient, mild, and highly stereoselective route to
â-lactones from aldehydes and readily available ketene
thiopyridylacetals. The simplicity and high diastereo-
2
(