Total synthesis of tetrahydrolipstatin and stereoisomers via a highly regio- and diastereoselective carbonylation of epoxyhomoallylic alcohols

Article abstract of DOI:10.1021/ja505639u

A concise enantioselective synthesis of tetrahydrolipstatin (THL) and seven stereoisomers has been achieved. The synthesis of THL was accomplished in 10 steps and 31% overall yield from an achiral ynone. Key to the success of the approach is the use of a bimetallic [Lewis acid]⁺[Co(CO)₄]^- catalyst for a late-stage regioselective carbonylation of an enantiomerically pure cis-epoxide to a trans-β-lactone. The success of this route to THL and its stereoisomers also demonstrated the practicality of the carbonylation catalyst for complex molecule synthesis as well as its functional group compatibility.

Full text of DOI:10.1021/ja505639u

Article
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Open Access on 07/08/2015
Total Synthesis of Tetrahydrolipstatin and Stereoisomers via a Highly
Regio- and Diastereoselective Carbonylation of Epoxyhomoallylic
Alcohols
Michael Mulzer,‡,§ Brandon J. Tiegs,‡,§ Yanping Wang,†,§ Geoffrey W. Coates,*,‡
and George A. O’Doherty*,†
†Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States
‡Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, New York 14853, United States
S
* Supporting Information
ABSTRACT: A concise enantioselective synthesis of tetrahy-
drolipstatin (THL) and seven stereoisomers has been
achieved. The synthesis of THL was accomplished in 10
steps and 31% overall yield from an achiral ynone. Key to the
success of the approach is the use of a bimetallic [Lewis
acid]+[Co(CO)4]− catalyst for a late-stage regioselective
carbonylation of an enantiomerically pure cis-epoxide to a
trans-β-lactone. The success of this route to THL and its
stereoisomers also demonstrated the practicality of the
carbonylation catalyst for complex molecule synthesis as well as its functional group compatibility.
asymmetric aldol,7 (3) asymmetric allylation/crotylation,8 (4)
INTRODUCTION
Tetrahydrolipstatin (THL, 1) is an over-the-counter anti-
■
asymmetric reductions,9 (5) asymmetric resolutions,10 (6)
asymmetric oxidations,11 and (7) chiron approach.12 These
obesity drug that acts by inhibiting the absorption of dietary
routes include the elegant use of a chiral phosphate template,9c
fats. THL is the saturated form of lipstatin (2), a natural
a tandem Mukaiyama aldol lactonization,7e,i an anti-aldol
segment via a non-aldol route,7h and a Prins cyclization for
stereocontrol.10b
product isolated from Streptomyces toxytricini in 1987.1 Due to
its greater stability, THL was chosen over lipstatin for
pharmaceutical development. Both THL and lipstatin contain
an α-alkylated β,δ-dihydroxy acid, which exists in the β-lactone
form (Figure 1). The β-lactone in THL and lipstatin is believed
As part of a larger effort aimed at the use of catalysis for the
asymmetric synthesis and structure−activity relationship studies
of biologically active natural products,14 we became interested
in the synthesis of THL (1) and related analogues 3 (Figure 1).
We were particularly interested in the carbonylation of epoxides
using bimetallic [Lewis acid]+[Co(CO)4]− catalysts, which has
recently emerged as a reliable, direct route to β-lactones.15 We
have had success using this type of carbonylation catalyst for
the synthesis of terminal β-lactones en route to natural
products.16 However, unsymmetrically disubstituted epoxides
are prone to giving a mixture of regioisomeric β-lactones.
Presumably this is because of an unselective SN2-ring opening
reaction in the case of electronically or sterically unbiased
substrates (Scheme 1).
This problem has recently been addressed by the
introduction of catalysts that can carbonylate racemic and
enantioenriched trans-disubstituted epoxides to the correspond-
ing cis-β-lactones with high and opposing regioselectivities.17
We hypothesized that it would be possible to obtain the desired
β-lactone isomer 3b of THL and its analogues via regioselective
carbonylation of protected cis-epoxyhomoallylic alcohols
Figure 1. Tetrahydrolipstatin (THL, 1), lipstatin (2), and analogues
(3).
to ring-open and covalently bind to pancreatic lipase, which
results in irreversible inhibition.1a,2 In addition, THL and
related β-lactones have been found to inhibit the thioesterase
domain of fatty acid synthase (FAS),3 the inhibition of which
has been linked to anticancer activity.4 More recently, THL has
been shown to inhibit the in vitro growth of Giardia duodenalis,
the causative parasite of the gastrointestinal disease giardiasis.5
Since the first synthesis of THL by Schneider,6a there have
been numerous total6−12 and formal syntheses of THL,13 which
have involved a diverse range of approaches. In terms of how
they derive absolute stereochemistry, these approaches can be
classified into the following categories: (1) chiral auxiliary,6 (2)
Received: June 10, 2014
© XXXX American Chemical Society
A
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[Lewis acid]+[Co(CO)4]− carbonylation catalyst with the
Lewis basic and Brønsted acidic formamide functional group
as well as the rather epimerizable α-amino ester group.
Scheme 1. Regioselective Carbonylation of Protected cis-
Epoxyhomoallylic Alcohols
RESULTS AND DISCUSSION
■
Formal Synthesis of Tetrahydrolipstatin. To ensure
success with this approach, we began our efforts with the
synthesis of the diastereomeric terminal epoxides 10 and 12
(Scheme 3). The approach began with a Leighton allylation20
a
Scheme 3. Formal Synthesis of THL (1)
(Scheme 1). Herein, we disclose a new route for the synthesis
of THL and seven stereoisomers using regioselective carbon-
ylation of epoxides to form the β-lactone moiety. The fatty acid
lipid portion of THL (4b) was prepared from protected cis-
epoxyhomoallylic alcohol 5b with all the lipid stereogenic
centers in place via a de novo asymmetric route (Scheme 2).
Scheme 2. Retrosynthetic Analysis of THL (1)
a
Reagents and conditions: (a) (S,S)-Leighton, Sc(OTf)3 (2.5 mol %),
CH2Cl2, −10 °C, 96%, >95% ee; (b) Boc2O, n-BuLi, THF, 0 °C, 93%;
(c) I2, MeCN, −20 °C, 67%; (d) K2CO3, MeOH, rt, 99%, >95% dr;
(e) MOMCl, DIPEA, CH2Cl2, 0 °C, 88%; (f) Co2(CO)8 (10 mol %),
3-hydroxypyridine (20 mol %), CO (900 psi), MeOH, THF, 60 °C,
89%; (g) PNBA, DIAD, PPh3, THF, 0 °C, 99%; (h) K2CO3, MeOH, 0
°C, 90%; (i) MOMCl, DIPEA, CH2Cl2, 0 °C, 95%; (j) Co2(CO)8 (10
mol %), 3-hydroxypyridine (20 mol %), CO (900 psi), MeOH, THF,
60 °C, 87%. DIAD = diisopropyl azodicarboxylate, PNBA = p-
nitrobenzoic acid, MOMCl = chloromethyl methyl ether, DIPEA =
N,N-diisopropylethylamine.
Retrosynthetic Analysis. Retrosynthetically, we envi-
sioned preparing THL from its lipid core 4b and N-formyl-L-
leucine (Scheme 2). Using a regioselective carbonylation
reaction, the lipid portion of THL (4b) could be prepared
either directly from cis-epoxyalcohol 5b or from 5a after
alkylation of the terminal β-lactone 4a. Epoxides 5a,b could be
prepared from a highly diastereoselective epoxidation of
homoallylic alcohol 6a,b, which in turn could be prepared
from 7a,b via asymmetric synthesis. Key to the success of this
approach is the need for high regioselectivity in the
carbonylation (5 to 4). Presumably, this could be accomplished
with a high degree of confidence using terminal epoxide 5a.15a
However, the subsequent alkylation of terminal β-lactones such
as 4a is highly problematic.10a,18 Consequently, a greater degree
of synthetic efficiency would result from a regioselective
carbonylation of a 2,3-disubstituted epoxide with all the
requisite lipid carbons in place, i.e. 5b to 4b. Regioselective
carbonylation of epoxides had very little precedence in the
synthesis of complex molecules prior to our endeavors.19
We anticipated that the precise choice of hydroxyl protecting
group in 5b could be critical for the control of the
carbonylation regioselectivity. At the outset, we chose a
methoxymethyl group (MOM) for its potential to participate
in chelated transition states. However, we were also interested
in investigating the use of N-formyl-L-leucine, thus avoiding the
need for a protecting group at this stage. This had the added
advantage of testing the compatibility of the
of dodecanal 7a to give homoallylic alcohol 6a. After Boc-
protection of alcohol 6a, the resulting t-butylcarbonate 8 was
treated with iodine to form cyclic carbonate 9. Hydrolysis of
carbonate 9 led to in situ epoxidation to form 10, which was
then protected as a MOM ether 5a (MOMCl/DIPEA).
Alternatively, the stereochemistry at C5 in 10 was inverted
using Mitsunobu conditions to give 12 after hydrolysis (PNBA/
PPh3/DIAD, K2CO3/MeOH), which was also protected as a
MOM ether 13. Epoxides 5a/13 underwent regioselective
carbonylation to give β-hydroxy esters 11/14 when exposed to
carbonylation conditions (CO, 10 mol % Co2(CO)8, 20 mol %
3-hydroxypyridine).21 The synthesis of β-hydroxy ester 14
constitutes a formal synthesis of THL (1) as 14 has been
previously transformed into THL via the n-hexyl α-alkylation of
a dianion generated from 14.12
Asymmetric Synthesis of cis-Epoxyhomoallylic Alco-
hol 19. With access to a formal synthesis of THL, we turned
our focus to potentially more efficient approaches to THL,
which involved carbonylation of the more challenging 2,3-
B
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disubstituted cis-epoxide 5b. The synthesis of epoxide 5b
required a practical asymmetric synthesis of epoxyhomoallylic
alcohol 19 (Scheme 4). Our approach involved the novel
Scheme 5. Synthesis of THL (1): Carbonylation of MOM-
Protected Epoxide 5b
a
a
Scheme 4. Synthesis of cis-Epoxyhomoallylic Alcohol 19
a
Reagents and conditions: (a) MOMCl, DIPEA, CH2Cl2, 0 °C, 85%;
a
Reagents and conditions: (a) (S,S)-Noyori (5 mol %), Et3N,
(b) [ClTPPAl][Co(CO)4] (1 mol %), CO (900 psi), THF, 50 °C,
81%; (c) BF3·OEt2, 1,2-ethanedithiol, CH2Cl2, 0 °C, 83%; (d) N-Cbz-
L-leucine, DCC, DMAP, CH2Cl2, rt, 93%; (e) Pd/C (10% wt/wt, 10
mol %), H2 (1 atm), AcOCHO, rt, 80%. ClTPP = meso-tetra(4-
chlorophenyl) porphyrinato, DCC = N,N′-dicyclohexylcarbodiimide,
DMAP = 4-dimethylaminopyridine.
HCO2H, rt, 83%, >95% ee; (b) H2N(CH2)3NH2, KH, 15 °C to rt,
80%; (c) TBSCl, imidazole, DMF, rt, 97%; (d) n-BuLi, HPMA, THF,
−20 °C; C6H13I, −20 °C to rt, 88%; (e) TBAF, THF, rt, 96%; (f) Pd/
CaCO3, quinoline, H2 (1 atm), MeOH, rt, 96%; (g) t-BuOOH,
VO(acac)2 (2 mol %), CH2Cl2, 0 °C, 94%, 92% dr. KAPA = potassium
3-aminopropylamide, TBSCl = tert-butyldimethylsilyl chloride, HMPA
= hexamethyl phosphoramide, TBAF = tetra-n-butylammonium
fluoride.
0.36, CHCl3);6b synthetic [α]D = −33.7 (c = 0.48, CHCl3))
23
consistent with what have been reported in the literature.
Alternative Approach to THL. To test the functional
group compatibility of the carbonylation catalyst, we explored
alternatives to the MOM protecting group. In this vein, we
looked at the use of the N-formyl-L-leucine ester group (i.e.,
22) (Scheme 6) as a replacement for the MOM ether. Along
construction of the Z-homoallylic alcohol functionality via a
Noyori reduction/alkyne zipper/Lindlar reduction sequence.22
To establish the absolute stereochemistry for this route, we
used a highly enantioselective (95% ee) Noyori asymmetric
reduction23 of achiral ynone 7b, which could be prepared in
one step from a known Weinreb amide. Using the alkyne zipper
reaction,24 the internal 2-alkyne in 15 was isomerized into a
terminal alkyne and then TBS protected to give 16. Alkylation
of terminal alkyne 16 (n-BuLi then n-Hex-I, 88%) and TBAF-
promoted deprotection of the TBS-ether provided the
homopropargyl alcohol 17. Partial hydrogenation of alkyne
17 using Lindlar conditions25 (1 atm H2, Pd/CaCO3, quinoline,
96%) cleanly gave (Z)-olefin 6b. Finally, a highly diaster-
eoselective hydroxy-directed epoxidation of 6b furnished 19 (t-
BuOOH, 2 mol % VO(acac)2, 94%, 92% dr) via putative
intermediate 18.26
Scheme 6. Synthesis of THL (1): A Late-Stage
a
Carbonylation of Epoxide
Total Synthesis of Tetrahydrolipstatin. With the
establishment of a practical and stereocontrolled synthesis of
epoxide 19, we began our investigation of the regioselectivity of
the carbonylation reaction (Scheme 5). This study began with
the protection of the alcohol as a MOM ether 5b (MOMCl,
85%). To our delight, when the MOM-protected epoxide 5b
was subjected to carbonylation (1 mol % [ClTPPAl]
[Co(CO)4], CO (900 psi)),15f a single regioisomer β-lactone
20 was formed, which was obtained in 81% isolated yield.
The synthesis of THL was easily finished via a four-step
deprotection/acylation/deprotection/formylation procedure.
Thus, the MOM group was removed with BF3 etherate to
give 4b (83%). A DCC coupling of 4b with N-Cbz-L-leucine
installed the amino acid side chain in 21. Finally, a two-step
hydrogenolysis/formylation procedure both removed the Cbz
group (1 atm H2, Pd/C in AcOCHO) and installed the N-
formyl group to give THL (1) without any epimerization (vide
infra).6f,7h The synthetic THL produced had spectral (1H, 13C
a
Reagents and conditions: (a) N-formyl-L-leucine, DCC, DMAP,
CH2Cl2, rt, 88%; (b) N-Cbz-L-leucine, DCC, DMAP, CH2Cl2, rt, 99%;
(c) Pd/C (10% wt/wt, 10 mol %), H2 (1 atm), THF, rt; DCC, formic
acid, CH2Cl2, rt, 79%; (d) [ClTPPAl][Co(CO)4] (2 mol %), CO
(900 psi), THF, 50 °C, 80%.
with testing the functional group compatibility of the
carbonylation conditions, this substitution also had the
advantage of reducing steps.
We initially investigated the synthesis of epoxide 22 via the
direct DCC coupling of N-formyl-L-leucine with 19. Unfortu-
nately, we were not able to find conditions under which the
coupling occurred without appreciable amounts of epimeriza-
20
NMR, IR) and optical properties (reported [α]D = −33 (c =
C
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a
tion (i.e., 22 and 23 were isolated as a 6:4 mixture of
epimers).6f,7h To circumvent the epimerization problem, we
returned to the less epimerizable N-Cbz-protected L-leucine.
Under the same DCC coupling procedure, N-Cbz-L-leucine
coupled with 19 to afford ester 24 in 99% yield without any
sign of epimerization.6f Exposure of 24 to the two-step
hydrogenolysis/formylation conditions (1 atm H2, Pd/C then
HCO2H/DCC) provided the desired epoxide 22 in 79% yield.
Gratifyingly, under carbonylation conditions (2 mol %
[ClTPPAl][Co(CO)4], CO (900 psi)), epoxide 22 with an
N-formyl-L-leucine side chain was cleanly transformed into
THL (1) as the single regioisomer, which was obtained in
excellent yield (80%) without any sign of epimerization.
Preparation of Other THL Stereoisomers. The
successful synthesis of THL via late-stage regioselective
carbonylation of epoxide 22 prompted us to explore the
scope of this approach. In particular, we were interested in
exploring its utility for the synthesis of various stereoisomers of
THL.27 To do this, we required access to a series of
stereoisomeric epoxides with various groups at the C5 position.
This was carried out from epoxyalcohol 19 and its enantiomer
ent-19. Thus, the C5 diastereomer 26 with a MOM-protecting
group was easily prepared from ent-19 by means of a three-step
Mitsunobu/hydrolysis/protection sequence in a 65% overall
yield (Scheme 7).
Scheme 8. Synthesis of Stereoisomeric Epoxides from 19
a
Reagents and conditions: (a) N-Cbz-D-leucine, DCC, DMAP,
CH2Cl2, rt, 96%; (b) Pd/C (10% wt/wt), H2 (1 atm), THF, rt;
DCC, formic acid, CH2Cl2, rt, 82%; (c) N-formyl-L-leucine, DIAD,
PPh3, THF, 0 °C to rt, 82%; (d) N-Cbz-D-leucine, DIAD, PPh3, THF,
0 °C, 93%; (e) Pd/C (10% wt/wt), H2 (1 atm), THF, rt; DCC, formic
acid, CH2Cl2, rt, 67%.
Scheme 9. Synthesis of Stereoisomeric Epoxides from ent-
a
19
a
Scheme 7. Synthesis of Diastereomer 26
a
Reagents and conditions: (a) PNBA, DIAD, PPh3, THF, 0 °C, 96%;
(b) K2CO3, MeOH, 0 °C, 80%; (c) MOMCl, DIPEA, CH2Cl2, 0 °C,
84%.
By both invertive and retentive acylation chemistry, the three
epoxides with an N-formyl leucine side chain (23, 28, and 30)
were prepared from epoxide 19 (Scheme 8). To circumvent the
problem associated with epimerization during the DCC
coupling with N-formyl leucine, we resorted to the use of N-
Cbz-D-leucine in the coupling to form 27, which could be
readily converted into N-formyl amide 23 by hydrogenolysis
followed by a DCC coupling with formic acid. In contrast to
the DCC coupling with N-formyl leucine, the invertive
Mitsunobu acylation of epoxide 19 with N-formyl leucine
occurred with complete stereocontrol to give 28. Epoxide 30
was also made from 19 via ester 29 by means of a three-step
Mitsunobu acylation and hydrogenolysis N-Cbz to N-formyl
group exchange (1 atm H2, Pd/C then HCO2H/DCC).
With related invertive and retentive acylation chemistry,
three stereoisomeric epoxides (ent-24, ent-29, and 32) and their
enantiomers were made with the N-Cbz leucine side chain from
epoxide ent-19 (Scheme 9). To serve as a control group for the
amide substitution, epoxide 31 with no amino-substitution was
prepared by a Mitsunobu acylation with isohexanoic acid.
We next investigated the regioselectivity of the carbonylation
with the various epoxide stereoisomers (Table 1). Exposure of
the MOM-protected diastereomeric epoxide 26 to typical
carbonylation conditions cleanly converted it into β-lactone 33
(entry 1, 88%) with complete regioselectivity. Similarly, clean
conversion was found for the C2″ stereoisomeric epoxide 23,
which reacted to give β-lactone 34 as a single regio- and
stereoisomer (entry 2, 77%). In contrast to changes in
a
Reagents and conditions: (a) isohexanoic acid, DIAD, PPh3, THF, 0
°C, 62%; (b) N-Cbz-D-leucine, DCC, DMAP, CH2Cl2, rt, 96%; (c) N-
Cbz-L-leucine, DIAD, PPh3, THF, 0 °C, 98%; (d) N-Cbz-D-leucine,
DIAD, PPh3, THF, 0 °C, 98%.
stereochemistry at C2″, the inversion of the stereochemistry
at C5 had a significant effect on the regioselectivity of the
reaction (entries 3 and 4). Epoxide 28 with an N-formyl amide
carbonylated to give β-lactones 35 in good yields of a 6:1
mixture of regioisomers. The C2″ epimeric epoxide 30 also
carbonylated with lower regioselectivity to give β-lactones 36 in
good yields of a 5:1 mixture of regioisomers. In addition to
poor regioselectivities, epoxides 28 and 30 also required higher
catalyst loadings.28
We hypothesized that the loss in regioselectivity for
substrates 28 and 30 could be the result of hydrogen bonding
interactions (Figure 2). This hydrogen bonding interaction in
turn could lower the barrier for pathway a to the regioisomeric
β-lactone. To test this hypothesis, we investigated the
carbonylation of epoxides 31, ent-24, ent-29, and 32. When
the N-formyl group was removed as in epoxide 31 (entry 5),
the carbonylation occurred to give β-lactone 37 with complete
D
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Table 1. Stereochemical Scope of Regioselective
a
Carbonylation
Figure 2. Rationale for loss of regiocontrol for epoxides 28 and 30.
Scheme 10. Synthesis of β-Lactones 35 and 36 from Known
a
β-Lactone 4b
a
Reagents and conditions: (a) N-Cbz-L-leucine, DIAD, PPh3, THF, 0
a
°C, 72%; (b) Pd/C (10% wt/wt), H2 (1 atm), THF, rt; DCC, formic
acid, CH2Cl2, rt, 63%; (c) N-Cbz-D-leucine, DIAD, PPh3, THF, 0 °C,
82%; (d) Pd/C (10% wt/wt), H2 (1 atm), THF, rt; DCC, formic acid,
CH2Cl2, rt, 60%.
See Supporting Information for detailed reaction conditions for each
b
1
entry. Ratio determined by H NMR spectroscopy; for entries 1, 2,
and 5−8 regioisomer a was not observed.
control of regioselectivity. Interestingly, when the N-formyl
group was replaced with the less acidic N-Cbz group, the high
regioselectivity returned. Thus, epoxides ent-24, ent-29, and 32
carbonylated to form β-lactones ent-21, ent-38, and ent-39 as
single regioisomers (entries 6−8; 75%, 80%, 74%, respectively).
In order to confirm the connectivity of unknown β-lactones
35, 36, 38, and 39, we prepared them independently from
known β-lactone 4b (Scheme 10). The β-lactone 4b was
converted into Cbz-protected leucine esters 38 and 39 via a
Mitsunobu esterification. A hydrogenolysis/formylation reac-
tion converted 38 and 39 into 36 and 35, respectively, which
had identical H NMR spectra to the products prepared from
the carbonylation reactions.
In support of the structure of the minor isomers formed from
the carbonylation of epoxides 28 and 30 (entries 3 and 4; 35
and 36), we carried out a thermolytic decarboxylation reaction
on the product mixture 35 and presumed regioisomer 35a
(Scheme 11). Specifically, a 2:1 mixture of 35 and hypothesized
35a was heated to 230 °C in a sealed tube under argon for 1
1
E
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epimerization that occurred during the DCC coupling of
epoxide ent-19 and N-formyl-L-leucine. Under these conditions,
a mixture of ent-22 and ent-23 was afforded, which upon
carbonylation were smoothly converted into a mixture of β-
lactones ent-1 and ent-34. Preparative HPLC was used to purify
the two isomers, ent-1 and ent-34. The remaining two
enantiomers, ent-35 and ent-36, were prepared by an analogous
route to the synthesis of their enantiomers (35 and 36, Scheme
10). This was accomplished by a two-step hydrogenolysis/
formylation procedure, which replaced the N-Cbz group with
an N-formyl group in β-lactones ent-38 and ent-39, cleanly
providing ent-36 and ent-35, respectively.
Scheme 11. Evidence for Minor Regioisomer 35a by
Thermolysis
a
CONCLUSIONS
■
A concise enantioselective synthesis of THL has been achieved
in 10 steps and 31% overall yield from achiral ynone 7b. The
route is amenable for the production of THL and seven
stereoisomers. In addition, the route demonstrated the
versatility and regioselectivity of the bimetallic [Lewis
acid]+[Co(CO)4]− catalyzed carbonylation of enantiomerically
pure cis-epoxides to trans-β-lactones. Further application of
bimetallic carbonylation catalysts for the synthesis and
medicinal chemistry studies of natural products will be reported
in due course.
a
Reagents and conditions: (a) 230 °C, 60%; (b) 1-octene, Grubbs II,
CH2Cl2, reflux, 59%, E/Z = 6:1; (c) N-formyl-L-leucine, DIAD, PPh3,
THF, 0 °C, 69%; (d) N-formyl-L-leucine, DIAD, PPh3, THF, 0 °C,
87%.
hour producing trans-olefin 40 as the sole product. The identity
of olefin 40 was confirmed by its synthesis from homoallylic
alcohol 41, which in turn was made from terminal olefin 6a
using cross metathesis.29 For comparison, cis-olefin 42 was
prepared from 6b, which was readily distinguishable from its
trans-isomer 40 by 13C NMR spectra.
Synthesis of ent-THL and Its Stereoisomers. With the
route established above, we synthesized the enantiomer of THL
(ent-1), as well as the stereoisomers ent-34, ent-35, and ent-36
(Scheme 12). The most direct route took advantage of the
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures, full characterization data,
and copies of spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
g.odoherty@neu.edu
coates@cornell.edu
Scheme 12. Synthesis of ent-THL (ent-1) and Its
Stereoisomers
a
Author Contributions
§M.M., B.J.T. and Y.W. are co-first authors; the order is
alphabetical.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is dedicated to the memory of Dr. Josephine (JoJo)
O’Doherty. We are grateful to NIH (Grant GM090259), NSF
(Grant CHE-1213596), and DOE (Grant DE-FG02-
05ER15687) for financial support of this research.
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dx.doi.org/10.1021/ja505639u | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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