Double diastereoselective, nucleophile-catalyzed aldol lactonizations (NCAL) leading to β-lactone fused carbocycles and extensions to β-lactone fused tetrahydrofurans

Article abstract of DOI:10.1021/ol101388h

A double diastereoselective variant of the nucleophile-catalyzed aldol lactonization (NCAL) process is described. This strategy delivers β-lactone-fused carbocycles with good to excellent diastereoselectivities using cinchona alkaloid catalysts with enantioenriched aldehyde acids, which gave low diastereoselectivity based on substrate control alone. β-Lactone-fused tetrahydrofurans are also prepared for the first time via the NCAL process; however, diastereoselectivity was only modestly improved when applying double diastereodifferentiation to these systems.

Full text of DOI:10.1021/ol101388h

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3764-3767
Double Diastereoselective,
Nucleophile-Catalyzed Aldol
Lactonizations (NCAL) Leading to
ꢀ-Lactone Fused Carbocycles and
Extensions to ꢀ-Lactone Fused
Tetrahydrofurans
Kay A. Morris, Kevin M. Arendt, Seong Ho Oh,† and Daniel Romo*
Department of Chemistry, Texas A&M UniVersity, P.O. Box 30012,
College Station, Texas 77842-3012
romo@tamu.edu
Received June 15, 2010
ABSTRACT
A double diastereoselective variant of the nucleophile-catalyzed aldol lactonization (NCAL) process is described. This strategy delivers ꢀ-lactone-
fused carbocycles with good to excellent diastereoselectivities using cinchona alkaloid catalysts with enantioenriched aldehyde acids, which
gave low diastereoselectivity based on substrate control alone. ꢀ-Lactone-fused tetrahydrofurans are also prepared for the first time via the
NCAL process; however, diastereoselectivity was only modestly improved when applying double diastereodifferentiation to these systems.
The significant utility of double diastereodifferentiation1 has
been demonstrated on numerous occasions in the context of
natural product total synthesis. Therefore, the importance of
this strategy cannot be overstated.2 Furthermore, the degree
to which a chiral reagent can influence stereochemical
outcomes by overcoming inherent substrate bias is revealed
through the study of double diastereodifferentiation.
The development of concise enantioselective routes to
ꢀ-lactones continues to be an active area of research because
of their varied reactivity and applications.3 Our recent
contributions to this area have focused on intramolecular,
nucleophile-catalyzed aldol lactonization (NCAL) processes
of aldehyde acids that provide convenient access to bicyclic
ꢀ-lactones bearing two or more stereogenic centers (Scheme
1a),4 building on elegant work by Wynberg and co-
† Present address: Codexis Laboratories Singapore Pte Ltd, 61 Science
Park Rd, Singapore, Singapore 117525.
(1) (a) Sharpless, K. B. Chem. Scr. 1985, 25, 71. (b) Masamune, S.;
Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem., Int. Ed. 1985, 24, 1.
(2) For some examples, see: (a) Katsuki, T.; Sharpless, K. B. J. Am.
Chem. Soc. 1980, 102, 5974. (b) Hentges, S. G.; Sharpless, K. B. J. Am.
Chem. Soc. 1980, 102, 4263. (c) Jacobsen, E. N.; Marko, I.; Mungall, W. S.;
Schroeder, G.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968. (d)
Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C. P.; Singh, V. K. J. Am.
Chem. Soc. 1987, 109, 7925. (e) For applications in aldol reactions, see:
Palomo, C.; Oiarbide, M.; Garcia, J. M. Chem. Soc. ReV. 2004, 33, 65.
(3) For reviews describing enantioselective ꢀ-lactone synthesis, see: (a)
Yang, H. W.; Romo, D. Tetrahedron 1999, 55, 6403. (b) Orr, R. K.; Calter,
M. A. Tetrahedron 2003, 59, 3545. (c) Paull, D. H.; Weatherwax, A.; Letcka,
T. Tetrahedron 2009, 65, 6771. (d) Purohit, V. C.; Matla, A. S.; Romo, D.
Heterocycles 2008, 76, 949. (e) For recent publications not included in these
reviews, see: Chidara, S.; Lin, Y.-M. Synlett 2009, 1675. (f) Wang, X.-N.;
Shao, P.-L.; Lv, H.; Ye, S. Org. Lett. 2009, 11, 4029. (g) Phillips, E. M.;
Wadamoto, M.; Scheidt, K. A. Synthesis 2009, 687.
10.1021/ol101388h  2010 American Chemical Society
Published on Web 08/12/2010

Scheme 1. Formation of Bicyclic and Tricyclic ꢀ-Lactones via
the NCAL Process from (a) Aldehyde Acids (1) and (b)
Ketoacids (4)
Figure 1. Observed diastereoselectivites for NCAL reactions leading
to ꢀ-lactone fused carbocycles 6-8 and proposed selectivity models.
workers.5 This process was previously rendered enanti-
oselective with the use of O-acetyl quinidine (O-AcQD)
or ꢀ-isocupreidine (ꢀ-ICPD) as chiral nucleophilic pro-
moters (chiral Lewis bases) to obtain enantioenriched
ꢀ-lactone fused cyclopentanes.4,6 More recently, the NCAL
process was extended to ketoacid substrates7 (Scheme 1b),
and a single example of a stoichiometric, enantioselective
reaction made use of tetramisole as a chiral promoter.8 In
addition, the utility of the NCAL process was demonstrated
in a concise, bioinspired, racemic,9 and subsequently enan-
tioselective10 total synthesis of salinosporamide A. Herein,
we demonstrate the utility and powerful stereochemical
influence of cinchona alkaloid catalysts in double diastereo-
selective NCAL reactions for the preparation of variously
substituted carbocycle-fused ꢀ-lactones. We also report the
first examples of tetrahydrofuran-fused ꢀ-lactones obtained
through the NCAL process.
substrates to determine if catalyst control could override
the low diastereoselectivities obtained with substrate
control alone (Figure 2).
Figure 2. Optically active nucleophiles (Lewis bases) employed
in the NCAL process.
We previously found that, with respect to the carboxylic
acid, ꢀ-substituted aldehyde acid and ketoacid substrates
provided bicyclic ꢀ-lactones (i.e., 6) with high diastereo-
selectivity (Figure 1). This observation provided evidence
for a NCAL process proceeding via ammonium enolate
intermediates based on A1,3-strain arguments, since a
[2 + 2] pathway proceeding through a ketene intermediate
would be expected to afford low diastereoselectivity.
However, substrates bearing substituents at other positions
(i.e., γ, δ) gave low diastereoselectivities as would be
predicted on the basis of the absence of A1,3 strain.7 This
led us to consider double diastereodifferentiation with
chiral nucleophiles, O-TMS quinidine (O-TMSQD) and
O-TMS quinine (O-TMSQN),11 with enantioenriched
We initiated double diastereodifferentiation studies with
previously studied carbocyclic substrates. Subjecting enan-
tiomerically enriched aldehyde acid (+)-9a12 (87% ee, chiral
HPLC) to standard NCAL conditions with Et3N as the
nucleophile resulted in a 2:1 mixture of anti/syn ꢀ-lactones
10a:10a′, respectively (Table 1, entry 1). Use of 10 mol %
O-TMSQD led to an increased level of diastereoselection
and complete reversal in diastereoselection to 1:7 anti/
syn ꢀ-lactones 10, and both relative and absolute stereo-
chemistry of the major ꢀ-lactone 10a′ was confirmed by
X-ray analysis (Table 1, entry 2).13 Alternatively, dia-
stereomeric ꢀ-lactone 10a′ could be obtained with high
diastereoselectivity (dr >19:1) employing O-TMSQN, indica-
tive of the matched case (Table 1, entry 3). Commercially
available dimeric catalysts, hydroquinidine 1,4-phthala-
zinediyl diether ((DHQD)2PHAL) and hydroquinine 1,4-
phthalazinediyl diether ((DHQ)2PHAL), were also studied
and provided similar results (Table 1, entries 4 and 5).
Since double diastereoselectivity was possible with γ-sub-
stituted aldehyde acid substrates, we next studied other
(4) (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) Oh, S. H.; Cortez, G. S.; Romo, D. J. Org. Chem. 2005, 70, 2835.
(5) Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166.
(6) For a review on cinchona organocatalysts, see: Marcelli, T.; Van
Maarseveen, J. J.; Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45, 7496
.
(7) Henry-Riyad, H.; Lee, C.; Purohit, V. C.; Romo, D. Org. Lett. 2006,
8, 4363.
(8) Purohit, V. C.; Matla, A. S.; Romo, D. J. Am. Chem. Soc. 2008,
130, 10478.
(12) For the preparation of optically active aldehyde acid substrates used
in this study and determination of enantiomeric purity, see Supporting
Information.
(9) Ma, G.; Nguyen, H.; Romo, D. Org. Lett. 2007, 9, 2143.
(10) Nguyen, H.; Ma, G.; Romo, D. Chem. Commun. 2010, 46, 4803.
(11) Calter, M. A. J. Org. Chem. 1996, 61, 8006.
(13) See Supporting Information for further details.
Org. Lett., Vol. 12, No. 17, 2010
3765

Table 1. Catalyst Screening for Double Diastereodifferentiation
with Aldehyde Acid (+)-9a
Table 2. Double Diastereoselective NCAL Reactions with
Enantioenriched Aldehyde Acids 9b-e
a Isolated yield. b Diastereomeric ratio determined by 1H NMR (500
MHz) of the crude reaction mixture. c Reaction was run for 48 h at 0.05
M. d Reaction was run for 72 h at 0.2 M.
enantiomerically enriched substrates with alternate substitu-
tion patterns. As previously reported and to serve as a
reference point, both enantiomers of the unsubstituted
bicyclic ꢀ-lactone 10b:10b′ were obtained with good enan-
tioselectivity employing the pseudoenantiomeric catalysts,
O-AcQD and ꢀ-ICPD, in 92% and 90% ee, respectively.4a
This example demonstrates the potential for significant
catalyst control in the NCAL process of aldehyde acids. As
expected, anti-silyloxy-ꢀ-lactone 10c′ derived from aldehyde
acid 9c was obtained with high diastereoselectivity (dr >19:
1) with Et3N as the nucleophilic promoter as a result of the
ꢀ-substituent (Table 2, entry 2). This substrate also provided
excellent efficiency. However, not surprisingly, diastereoselec-
tivity could not be altered with either O-TMSQD or O-TMSQN
because of the strong conformational bias exerted by allylic
1,3-strain (see Figure 1) but rather led only to greatly reduced
conversion. Use of Et3N with the γ,δ-substituted aldehyde acid
9d gave low diastereoselectivity leading to a 2:1 mixture of
ꢀ-lactones 10d:10d′ (Table 2, entry 3). Reversed diastereose-
lectivity (dr 1:3) was obtained with O-TMSQD, providing
ꢀ-lactone 10d′ as the major diastereomer but with low yield
(32%). However, use of O-TMSQN gave both improved yields
and diastereoselectivity (dr 10:1) with ꢀ-lactone 10d as the
major diastereomer, suggestive of a matched case. Double
diastereodifferentiation was also possible with cyclohexyl-fused
ꢀ-lactones 10e:10e′, which improved a 2:1 diastereomeric ratio
obtained with Et3N to complete catalyst control with O-TMSQN
leading to high diastereoselectivity (>19:1); however, conver-
sions were low (Table 2, entry 4).
a Reaction was run for 12-24 h at 0.05 M. b Yields refer to isolated, purified
products; diastereomeric ratios were determined by 1H NMR (500 MHz)
analysis (integration) of the crude reaction mixtures. c Reaction was run for
48-72 h at 0.20 M. d Previously described (see refs 4b and 4c) enantioselective
NCAL process with an achiral substrate shown for comparison. e Reaction was
run with O-AcQD. f Reaction was run with ꢀ-ICPD.
after extensive optimization studies, only low yields were
obtained using Et3N leading to γ- or δ-substituted tetrahy-
drofurans along with attendant low diastereoselectivies as
expected in analogy to cyclopentyl systems (Table 3, entries
1, 2). More tractable ketoacid substrates (e.g., 11, R ) Me)
delivered the highest yields with the use of 4-pyrrolidinopy-
ridine (PPY) leading to ꢀ-lactones 12c:12c′ as a 1:1 mixture
of diastereomers (Table 3, entry 3). The relative stereochem-
istry of ꢀ-lactone 12c′ was confirmed by single crystal X-ray
analysis (Figure 3). In the case of tetrahydropyran-fused
In the context of a total synthesis effort, we explored the
NCAL process for the synthesis of tetrahydrofuran-fused
ꢀ-lactones14 (e.g., 12). Initial studies toward these bicycles
provided access to racemic tetrahydrofuran- and tetrahydro-
pyran-fused ꢀ-lactones 12a-d:12a′-d′ (Table 3). However,
(14) For previous reports of tetrahydrofuran-fused ꢀ-lactones obtained
via (a) lactonization of ꢀ-hydroxy acids, see: Crich, D.; Hao, X. J. Org.
Chem. 1999, 64, 4016. (b) Presumed [2 + 2] cycloadditions, see: Brady,
W. T.; Giang, Y. F.; Marchand, A. P.; Wu, A. J. Org. Chem. 1987, 52,
3457.
Figure 3. Single crystal X-ray structure (ORTEP representation)
of tetrahydrofuran-fused ꢀ-lactone 12c′.
3766
Org. Lett., Vol. 12, No. 17, 2010

with cinchona alkaloid catalysts along with the consistently
low yields of tetrahydrofuran-fused ꢀ-lactones obtained via
the NCAL process, despite extensive optimization studies,
precluded further investigations of double diastereodiffer-
entiation with this class of substrates.
Table 3. Tetrahydrofuran- and Tetrahydropyran-Fused
ꢀ-Lactones 12 via the NCAL Process
Scheme 2. Attempted Double Diastereoselective Synthesis of
Tetrahydrofuran-Fused ꢀ-Lactones 12e/12e′
In summary, double diastereodifferentiation via the NCAL
process is possible with cinchona alkaloid catalysts and
enantioenriched aldehyde acids. In particular, carbocycle-
fused ꢀ-lactones were highly amenable to double diastereo-
differentiation leading to improvements in diastereoselec-
tivities from 1:1-2 to >19:1 in several cases. This process
thus enables access to highly functionalized carbocycles with
existing stereocenters to be obtained with high diastereose-
lectivity. Tetrahydrofuran-fused ꢀ-lactones were accessed for
the first time via the NCAL process; however, prospects for
double diastereodifferentiation were precluded because of
low reaction yields. These studies reveal the exquisite
stereochemical control exerted by the cinchona alkaloids in
the NCAL process given the ability of these catalysts to
override inherent substrate bias and in some cases reverse
diastereoselectivity obtained from substrate control alone.
a Yields refer to isolated, purified products; diastereomeric ratios were
determined by 1H NMR analysis (integration) of the crude reaction mixtures.
b Reaction was run at -30 °C. c PPY (1.5 equiv) was used as nucleophile
and i-Pr2NEt (2.0 equiv) as base. d Reaction was run at 0 °C.
ꢀ-lactone 12d, high diastereoselectivity was observed, how-
ever, in low yield (Table 3, entry 4). The presence of an
oxygen atom in the tether likely alters reactive rotamer
populations, and a change in mechanism is possible, espe-
cially with R-oxygenated acid substrates leading to ketene
intermediates, e.g., [2 + 2] cycloadditions, which may
account for lower yields in these reactions.
While cinchona alkaloid catalysts proved useful for double
diastereodifferentation leading to carbocyclic systems, they
were less successful when applied to aldehyde acids bearing
oxo-linkages (Scheme 2). For example, racemic aldehyde
acid 11e provided 47% yield of a 1:1 mixture of diastere-
omeric tetrahydrofuran-fused ꢀ-lactones 12e:12e′ employing
Et3N.15 Attempted double diastereodifferentation with O-
TMSQD and racemic 11e gave low enantioselectivity for
both diastereomers (dr 2:1), indicating that effective catalyst
control did not occur with this substrate and thus diastereo-
selectivity would not be expected to improve when employ-
ing enantioenriched substrate. Similar results were obtained
with O-TMSQN (not shown). These initial results obtained
Acknowledgment. We gratefully acknowledge NIH
(GM069784), NSF (CHE-0809747, partial support), and the
Welch Foundation (A-1280) for support. K.A.M. gratefully
acknowledges an American Chemical Society Division of
Organic Chemistry Graduate Fellowship sponsored by Eli
Lilly and a Bristol-Myers Squibb Minority Chemist Fellow-
ship award. K.M.A. acknowledges support from TAMU
Undergraduate Research and the American Chemical Society
Scholars Programs. We thank Mr. Gang Liu for development
of a procedure for the synthesis of aldehyde acids 9a and
9d. We thank Dr. Joe Reibenspies (TAMU) and Dr. Nattamai
Bhuvanesh (TAMU) for X-ray crystallographic analysis.
Supporting Information Available: Experimental pro-
1
cedures and full characterization (including H and 13C
spectra and stereochemical proofs) for aldehyde acids 9a,
9c-e, and 11a-e, carbocyclic ꢀ-lactones 10a:10a′, 10c-e:
10c′-e′, and tetrahydrofuran-fused ꢀ-lactones 12a-e:
12a′-e′. X-ray crystallographic data for compounds 10a′ and
12c′ are also provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
(15) R,ꢀ-Unsaturated aldehydes I and II were isolated as byproducts as
a result of competitive ꢀ-elimination of the corresponding aldehyde acid
starting material.
OL101388H
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