The total synthesis of (-)-tetrahydrolipstatin

Article abstract of DOI:10.1071/CH03121

Careful control during the bromolactonization of β,γ-unsaturated acid (4) was required to regioselectivity afford the trans-β-lactone (3) as the major diastereomer. Radical debromination of (3) followed by a three-step sequence of reactions afforded the lipase inhibitor (-)-tetrahydrolipstatin (1).

Full text of DOI:10.1071/CH03121

CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2003, 56, 795–803
The Total Synthesis of (–)-Tetrahydrolipstatin
Jennifer A. Bodkin,A Edward J. HumphriesA and Malcolm D. McLeodA,B
A School of Chemistry, F11, University of Sydney, Camperdown 2006, Australia.
B Author to whom correspondence should be addressed (email m.mcleod@chem.usyd.edu.au).
Careful control during the bromolactonization of β,γ-unsaturated acid (4) was required to regioselectively afford
the trans-β-lactone (3) as the major diastereomer. Radical debromination of (3) followed by a three-step sequence
of reactions afforded the lipase inhibitor (–)-tetrahydrolipstatin (1).
Manuscript received: 5 May 2003.
Final version: 19 May 2003.
Introduction
effect for the synthesis of this structural unit. Davies and
coworkers[19] performed the aldol addition of a chiral iron
octanoyl complex to a chiral aldehyde followed by oxidative
decomplexation of the iron auxiliary to give a β-lactone inter-
mediate with high selectivity and in 52% yield.A formal total
synthesis of a related intermediate has also been reported[20]
involving the aldol addition of the lithium enolate derived
from 1-octanoylbenzotriazole to an aldehyde, the product of
which underwent lactonization on acidic workup to give the
product with 4 : 1 diastereoselectivity and low yield.
Tetrahydrolipstatin (1), Diagram 1, is a potent inhibitor of
pancreatic lipase and used clinically as an anti-obesity drug
under the trade name Xenical. It is the saturated derivative of
lipstatin, which was isolated from Streptomyces toxytricini
in 1987.[1,2] The biological activity of (1) arises from the
β-lactone fragment of the molecule, which reacts to form a
persistent ester linkage with the serine hydroxyl group in the
active site of pancreatic lipase. This slows the rate at which
the intestine can absorb dietary triglycerides.[3,4]
Our own strategically distinct approach to (1), which also
aimed to exploit this efficiency, is outlined in Scheme 1. In a
retrosynthetic sense, tetrahydrolipstatin (1) can be obtained
via a three-step sequence from the known hydroxy lactone
(2).[9,12] It was envisaged that this lactone could be obtained
from bromolactone (3) by radical debromination and that (3)
in turn could be afforded from hydroxy acid (4) by bromolac-
tonization. In support of this proposal, there is considerable
precedent for the synthesis of trans-β-lactones such as (3)
from 2-substituted β,γ-unsaturated acid precursors related to
(4).[22–24] We also anticipated that the electronic influence
of the adjacent allylic alcohol functionality would favour
formation of β-lactone regioisomers over their γ-lactone
counterparts. The recent evaluation of the kinetics associated
with the radical reduction of related brominated β-lactones
by Crich[25] pointed to the viability of the subsequent radi-
cal dehalogenation step. The pivotal intermediate in our
approach, hydroxyacid(4), couldbeobtainedfromcyclicsul-
fite(5)intwostepsbydiorganocuprate-mediatedSNꢀ reaction
followed by ester hydrolysis. This cyclic sulfite (5) could be
derived from its parent diol, which could in turn be afforded
enantio- and regio-selectively from diene ester (6) by Sharp-
less asymmetric dihydroxylation (AD).[26] Reported here is a
novel enantio- and diastereo-selective synthesis of (1) based
on this strategy together with our observations concerning
the factors that control the regio- and stereo-selectivity of the
pivotal bromolactonization step. Aspects of this synthesis
have been reported in a recent communication.[27]
There has been considerable interest in tetrahydrolipstatin
due to the growing awareness of obesity-related illness and
several syntheses have been reported.[5–21] In each case the
construction of the strained trans-β-lactone of (1) emerges
as an important synthetic challenge. The majority of pre-
viously reported syntheses[5–16] use Adams’ conditions for
formation of the β-lactone from a β-hydroxy carboxylic acid
precursor. This requires establishment of the hydroxy acid
stereochemistry prior to lactone ring synthesis.
From a strategic viewpoint, greater efficiency would
be anticipated in approaches that couple β-lactone ring
formation with concomitant introduction of the required
stereochemistry and a number of innovative syntheses have
capitalized on this tactic. Kocienski and coworkers[17,18]
have reported the Lewis acid promoted [2 + 2] cycload-
dition of a 2-trimethylsilylketene with a chiral aldehyde,
followed by desilylation, to install the trans-β-lactone of (1)
in moderate yield and with 9 : 1 diastereoselectivity. Tandem
aldol-lactonization sequences have also been applied to good
NHCHO
(1)
O
O
O
O
Diagram 1.
© CSIRO 2003
10.1071/CH03121
0004-9425/03/080795

796
J. A. Bodkin, E. J. Humphries and M. D. McLeod
O
OH
O
NHCHO
O
(a)
C11H23
OR
C11H23
OR
O
O
3 steps
(7) R = Et
(11) R = Me
(8) R = Et
(12) R = Me
OH
O
O
OH
O
C11H23
C11H23
C6H13
C6H13
(b)
(1)
(2)
radical debromination
O
C11H23
OH
O
(c) for (9) or
(d) for (13)
OR
C11H23
OR
O
O
O
bromolactonization
O
S
OH
O
OH
O
R2
(10) R = Et, R2 = Bu
(9) R = Et
(13) R = Me
C11H23
OH
C11H23
C6H13
(14) R = Me, R2 = Hex
(4)
(3)
C6H13
Br
Scheme 2. Reagents and conditions: (a) AD-mix-α, methanesulfon-
amide, But OH/H2O, 0◦C, 32 h; (b) SOCl2, CCl4, ꢀ, 3 h; (c) CuCN,
BunLi, THF, −78◦C to room temperature, 15 min, then BF3 · OEt2,
−78◦C, 15 min; then (9), −78◦C, 30 min; (d) CuCN, HexnLi THF
−78◦C to room temperature, 15 min; then BF3 · OEt2, −78◦C, 15 min;
then (13), −78◦C, 30 min.
1. substitution
2. ester hydrolysis
1. Sharpless AD
2. sulfite formation
O
O
C11H23
OR
C11H23
OR
O
O
(5)
(6)
O
S
chloride (MTPA) ester derivatives. The modified Mosher’s
method[32] was used to unambiguously establish the abso-
lute configuration at C5 as (S). Although not discernable in
the parent alcohol (10), the MTPA ester derivatives also con-
firmed the (E)-configuration of the double bond based on
the large (15 Hz) coupling constant between the double-bond
protons. Finally, in order to confirm that the cuprate addition
had indeed proceeded to give the expected anti-diastereomer,
the circular dichroism spectrum was recorded. It has been
reported that the absolute configuration of the 2-position
of 2-alkyl-β,γ-unsaturated esters such as (10) gives rise to
a characteristic sign in the n → π∗ Cotton effect observed
between 200 and 260 nm.[33] This method confirmed the (2S)
absolute configuration and thus the C2–C5 anti-relationship
of (10) as shown. Thus, our initial foray into the synthesis of
(1) established the viability of the SharplessAD and diastere-
oselective cuprate substitution reactions for constructing the
required stereochemical array in ester (10).
With these preliminary results in hand, synthesis of (1)
began in earnest. When scaling up the synthesis, two changes
were incorporated: replacement of the butyl with the desired
hexyl sidechain; and the minor change from an ethyl ester to
a methyl ester.The latter change was made in response to pre-
liminary experimentation, revealing that the ethyl ester was
difficult to hydrolyze to the carboxylic acid in high yield. The
methyl ester was expected to be more readily cleavable, given
the wide range of procedures effective on methyl esters[34]
including those based on nucleophilic substitution.[35–37] Our
synthesis started with diene ester (11), obtained in 76%
yield by the Horner–Wadsworth–Emmons[29] coupling of
(2E)-4-(diethoxyphosphinyl)butenoic acid, methyl ester,[38]
and dodecanal. Formation of the diol (12) and its sub-
sequent conversion to the cyclic sulfites (13) followed the
previously developed conditions, and SꢀN substitution using
the diorganocuprate reagent derived from n-hexyllithium
afforded (14) with an improved 61% overall yield from
diene (11).
Scheme 1.
Results and Discussion
Our synthesis started with diene ester (7), obtained in
76% yield by the Horner–Wadsworth–Emmons coupl[i2n8g]
of (2E)-4-(diethoxyphosphinyl)butenoic acid, ethyl ester,
and dodecanal using the method developed by Takacs.[29]
Sharpless asymmetric dihydroxylation of diene (7) with the
commercially available AD-mix-α and methanesulfonamide
in tert-butanol/water proceeded smoothly to regioselectively
afford the (4S,5S)-diol (8) in 56% yield (Scheme 2).[26]
Treatment of diol (8) with thionyl chloride provided an insep-
arable mixture of diastereomeric cyclic sulfites (9) (93%).[30]
Given that the newly introduced stereocentre would be
removed in the subsequent cuprate substitution, the mixture
was used without separation.
The readily available diorganocuprate reagent obtained
from copper(i) cyanide, n-butyllithium, and boron trifluoride
diethyl etherate was added to sulfites (9). Initial attempts at
this addition were foiled by cuprate instability during reagent
transfer, leading to either significant formation of diene (7) by
a reductive elimination pathway or decomposition of starting
material.After much experimentation it was discovered that a
dry-ice jacketed cannula for the transfer of the cuprate would
prevent reagent decomposition and ester (10) was prepared
in 78% yield. Inspection of the 1H and 13C NMR spectra of
(10) indicated that a single diastereomer was formed.
The stereocontrol for this alkylation arises from the sub-
ꢀ
stitution occurring in an SN fashion, such that the new
substituent at C2 is delivered anti to the leaving group at
C4.[31] Confirmation of the stereochemistry of (10) was
given by a combination of techniques. The e.e. of (10),
and thus the enantioselectivity of the Sharpless AD reac-
tion, was determined as greater than 90% by NMR analysis
of both (R)- and (S)-methoxy-(trifluoromethyl)phenylacetyl
To our dismay, all attempts to hydrolyze the methyl
ester (14) proved unsatisfactory under a wide range of

The Total Synthesis of (–)-Tetrahydrolipstatin
797
OH
O
O
O
OH
O
(a)
(a),(b)
C11H23
OMe
C11H23
OMe
C11H23
OTce
C11H23
OH
(11)
(18)
(19)
C6H13
(14)
C6H13
(4)
(c)-(e)
(b)
OH
O
OH
O
OTBS
O
OTBS
O
(f)
(c)
C11H23
OH
C11H23
OTce
C11H23
OH
C11H23
OMe
(4)
C6H13
C6H13
C6H13
(17)
(16)
C6H13
Scheme 4. Reagents and conditions: (a) KOH(aq), THF, ꢀ, 22 h; (b)
(COCl)2, DMF (cat.), CH2Cl2, 0 to 25◦C, 1 h; then HOCH2CCl3, Et3N,
DMAP, room temperature, 20 h; (c)AD-mix-α, NaHCO3, But OH/H2O,
0◦C, 25 h; (d) SOCl2, CCl4, ꢀ, 22 h; (e) CuCN, HexnLi THF −78◦C to
room temperature, 15 min; then BF3 · OEt2, −78◦C, 20 min; then cyclic
sulfites, −78◦C, 1 h; (f ) Zn, AcOH, room temperature, 4 h.
OH
O
C11H23
OMe
C6H13
(15)
Scheme3. Reagentsandconditions:(a)(CH3)3SiOK,THF, roomtem-
perature, 25 h; (b) TBSCl, imidazole, DMF, room temperature, 90 h;
(c) Ba(OH)2 · 8 H2O, MeOH, room temperature, 64 h.
Synthesis of hydroxy ester (19) from diene (18) proceeded in
three steps as described for the ethyl and methyl series (47%
overall). Pleasingly, hydrolysis of this ester occurred using
zinc and acetic acid to afford the desired hydroxy acid (4) in
74% yield.[45]
protocols, including Ba(OH)2·8 H2O, LiOH, K2CO3, KOH,
(CH3)3SiOK,[39] Na/Ph2Se2,[37] 1 M HCl, high pressure,[40]
and a selection of enzymatic procedures based on lipases
derived from Pseudomonas, Candida rugosa, and Candida
antarctica.[41,42] The failure of the lipase-mediated proce-
dures to effect the transformation was particularly ironic
given the biological activity of our ultimate target (1). In
the best case (4) was obtained in only 16% yield using
(CH3)3SiOK, while the other protocols generally resulted in
no reaction or worse, isomerization to the conjugated ester
(15), orthecorrespondingcarboxylicacidundermoreforcing
conditions (Scheme 3).
Our initial proposal for circumventing this difficulty was
to protect the C5 hydroxyl of (14) and investigate the hydro-
lysis of this modified substrate, or a more lengthy sequence
based on reduction of the ester to the primary alcohol
followed by oxidation to the carboxylic acid. Protection
of (14) as its tert-butyldimethylsilyl (TBS) ether afforded
(16) in 89% yield. Subjecting this substrate to hydro-
lysis using Ba(OH)2·8 H2O in methanolsurprisinglyafforded
TBS-protected acids (17) in near quantitative yield (97%),
however careful examination of its 13C NMR spectrum indi-
cated that substantial epimerization adjacent to the carbonyl
group had occurred under these conditions. Furthermore, the
TBS group could not be cleanly removed under a range of
conditions including HF/acetonitrile, tetrabutylammonium
fluoride, or boron trifluoride diethyl etherate.[43] After decid-
ing to attempt a later deprotection, TBS-protected carboxylic
acid (17) was submitted for bromolactonization but frus-
tratingly yielded intractable mixtures of non-polar products
under standard bromolactonization conditions.[44]
Bromolactonization was initially conducted using the
method of Barnett[44] giving an unexpected result. A solu-
tion of the acid (4), in a biphasic mixture of dichloromethane
and 10% aqueous sodium hydrogen carbonate, was treated
with bromine in carbon tetrachloride. These conditions fur-
nished the β-lactones in a 2 : 1 ratio of the undesired cis-(3) to
trans-(3) (Scheme 5). The formation of β-lactones was con-
firmed by the presence of a strong absorption in its infrared
spectrum at 1830 cm−1 with no evidence of γ-lactone prod-
ucts being observed.[46] Identification of the diastereomers
was facilitated by 1H NMR analysis: β-lactone ring protons
have characteristic coupling constants and the observed val-
ues of 6.1 and 3.9 Hz for cis-(3) and trans-(3) respectively
were in agreement with literature values.[47]
The control of regiochemistry in the key bromolactoniza-
tion step was a pleasing result, as β,γ-unsaturated acids typ-
ically yield mixtures of β- and γ-lactone regioisomers.[22,23]
This high regioselectivity is thought to arise due to the influ-
ence of the inductively withdrawing C5 hydroxyl group,
which disfavours substitution at the adjacent C4 position
of the bromonium ion intermediate that leads to γ-lactone
products. Unexpected however, was the preference for the
cis-substituted lactone cis-(3), which precedent suggested
would be the disfavoured stereoisomer.[22,23] We suggest that
in addition to exerting a positive influence on the regio-
chemistry of the bromolactonization, the hydroxyl-bearing
C5 stereocentre also influences the diastereoselectivity of the
transformation under these reaction conditions.
After consideration of these difficulties, it was decided
to pursue a more readily removable ester. The trichloroethyl
(Tce) ester group seemed an ideal candidate as its
removal is performed by zinc reduction under mildly acidic
conditions.[45] Ester (11) was treated with aqueous potas-
sium hydroxide in tetrahydrofuran to afford the carboxylic
acid in 86% yield, which was immediately converted to the
trichloroethyl ester (18) in excellent yield (94%, Scheme 4).
Further experimentation led to an intriguing result. By car-
rying out the bromolactonization of (4) using methanol as the
organic cosolvent, instead of dichloromethane, a reversal of
the diastereoselectivity was observed. Optimization of these
conditions furnished 6 : 1 selectivity for the desired trans-(3),
as determined by H NMR analysis of the crude mixture,
and in high yield. In this case, the polar protic cosolvent
reduces the stereochemical influence of the C5 stereocentre
1

798
J. A. Bodkin, E. J. Humphries and M. D. McLeod
O
Hydroxy lactone (2) was esterified with N-benzyloxy-
carbonyl-l-leucine using 1,3-dicyclohexylcarbodiimide and
4-dimethylaminopyridine to afford ester (20) {[α]D −23 (c
1.1, CHCl3); lit.[9] [α]D −23.86 (c 1.06, CHCl3)} in 87%
yield.[9,12] Hydrogenolysis of the benzyloxycarbonyl group
was effected using 10% palladium on charcoal[9,12] and
the crude product was formylated with formic acetic
anhydride[9,12] to produce tetrahydrolipstatin (1) {[α]D −32
(c 1.8, CHCl3);lit.[2] [α]D −32(c 1, CHCl3)}in76%overtwo
steps. All spectral data for the synthetic (–)-(1) are identical
to that reported previously.[5–16]
OH
O
H
C11H23
C6H13
H
Br
Br
OH
O
trans-(3)
(a) or (b)
J 3.9 Hz
C11H23
OH
O
(4)
C6H13
OH
O
H
C11H23
C6H13
H
cis-(3)
J 6.1 Hz
O
Conclusion
HN
O
O
Ph
(c)
(–)-Tetrahydrolipstatin (1) was prepared in 12 steps and
11.3% yield from ester (11). Bromolactonization afforded of
the desired β-lactone regioisomers in quantitative yield and
careful choice of solvent and reaction time facilitated good
control over the lactone ring stereochemistry (6 : 1 trans/cis
ratio).
O
O
O
O
OH
O
(d)
C11H23
C11H23
C6H13
C6H13
(2)
(20)
(e), (f)
Experimental
tetrahydrolipstatin (1)
Optical rotations were measured using a PolAAR 2001 polarimeter
set at the 589.3 nm sodium d-line, in a 0.25 dm cell, in the indicated
solvent, and at the indicated concentration (g per 100 mL) and tem-
Scheme 5. Reagents and conditions: (a) Br2 in CCl4, DCM,
NaHCO3(aq), room temperature, 5 min, 1 : 2 trans-(3)/cis-(3); (b)
Br2 in CCl4, MeOH, NaHCO3(aq), room temperature, 20 s, 6 : 1
trans-(3)/cis-(3); (c) DBPO, Ph2Se2, Bu3SnH, PhMe, 0◦C, 2.5 h; (d)
Cbz-Leu, DCC, DMAP, CH2Cl2, room temperature, 1.5 h; (e) H2,
10% Pd-C, THF, room temperature, 3 h; (f ) AcOCHO, ether, room
temperature, 20 min.
perature. Specific rotations are quoted in 10−1 deg cm2 −1. Infrared
g
absorption spectra were obtained using a Perkin–Elmer 1600 series
Fourier transform infra-red spectrometer. Compounds were prepared
as thin films between 0.5 cm NaCl plates seated on a custom-made
perch in the apparatus. Absorption maxima are expressed in wavenum-
bers. 1H NMR spectra were recorded in CDCl3 using a Bruker AC
200B (1H: 200.13 MHz), Avance 200 (1H: 200.13 MHz), Avance 300
(1H: 300.13 MHz; 13C: 75.5 MHz) or DRX 400 (1H: 400.21 MHz; 13C:
100.6 MHz) spectrometer. 13C NMR spectra were recorded with com-
plete proton decoupling. NMR data is expressed as parts per million
downfield shift from tetramethylsilane, using residual chloroform (δH
7.26 ppm; δC 77.0 ppm) as an internal reference. All 1H–1H coupling
constants (in Hz) and multiplicities reported are apparent. High- and
low-resolution mass spectra were recorded using electron impact (EI)
or electrospray ionization (ESI). Major fragments are quoted as mass
to charge ratio (assignment, percentage of base peak). EI mass spectra
were recorded on a Finnigan PolarisQ ion trap mass spectrometer using
electron impact ionization mode or a VG Autospec mass spectrome-
ter. ESI mass spectra were recorded on a Finnigan LCQ ion trap mass
spectrometer, Finnigan MAT 900XL mass spectrometer, or a Bruker
Apex FT-ICR mass spectrometer. Analytical thin layer chromatography
(TLC)wasperformedusing0.2mmthick, aluminium-backed, precoated
silica gel plates (Merck Silicagel 60 F254). Flash chromatography was
performed using Merck Silicagel 60 (230–400 mesh ASTM), under
a positive pressure of nitrogen, with the indicated solvents. Solvent
compositions were mixed (v/v as specified). Moisture-sensitive reac-
tions were carried out in oven-dried glassware under a dry nitrogen
atmosphere. Powdered 4 Å molecular sieves were activated in a muffler
oven at 500◦C for 3 d and allowed to cool under desiccation before use.
Organolithium concentrations were determined by volumetric titration
against 2-butanol using 1,10-phenanthroline as indicator. All extracts
were dried over magnesium sulfate.
and the influence of the C2 stereocentre dominates, thereby
favouring the formation of trans-(3).[22–24] Purification of the
β-lactones on a silica column resulted in substantial decom-
position, affording only the trans-β-lactone in 13% yield. As
a result of this instability the crude mixture was carried on to
the next step.
Radical debromination of crude lactones (3) (Scheme 5)
was initially carried out with tributyltin hydride at low tem-
perature, using triethylborane[48] in the presence of dry air
as initiator. This reaction required repeated addition of initia-
tor and afforded the desired product (2) in 63% yield on one
occasion. Despite this initial success, the procedure was not
reproducible, typically leading to the recovery of unreacted
starting material and traces of debrominated material.The use
of 9-borabicyclo[3.3.1]nonane[49] under an inert atmosphere
as initiator was also investigated, however this also gave vari-
able results. Finally we investigated the radical reduction
conditions developed by Crich and Mo[25] using tributyltin
hydride in combination with diphenyldiselenide and di-tert-
butylperoxyoxalate (DBPO, CAUTION!)[50] as the initiator.
This protocol afforded trans-β-lactone (2) {[α]D −16 (c 1.4,
CH2Cl2); lit.[12] [α]D −15.3 (c 1.2, CH2Cl2)} in 63% yield
from the acid (4). The product derived from debromination
of cis-(3) was not observed. This can be rationalized by the
greater ring strain associated with the cis-isomer promoting
more rapid radical β-scission during the debromination reac-
tion, or the greater instability of the cis-lactone compounds
under the reaction conditions.
(2E,4E)-Hexadecadienoic Acid, Ethyl Ester (7)[51]
To stirring (2E)-4-(diethoxyphosphinyl)butenoic acid, ethyl ester[28]
(2.69 g, 10.8 mmol) was added 4 Å molecular sieves (11.5 g) and lithium
hydroxide (0.257 g, 10.7 mmol). The mixture was placed under nitro-
gen and a solution of dodecanal (1.42 g, 7.70 mmol) in tetrahydrofuran
(51.2 mL) was added. The reaction was heated at reflux for 16 h.
The reaction was filtered through silica, washed with dichloromethane
(50 mL) then diethyl ether (50 mL), and concentrated to afford a yellow

The Total Synthesis of (–)-Tetrahydrolipstatin
799
oil. Purification by flash chromatography (10% ethyl acetate/hexane)
afforded ester (7) as a yellow oil (1.64 g, 76%). RF 0.52 (25% ethyl
acetate/hexane). δH (200 MHz) 7.26 (1 H, m, CH CHCO2), 6.20–6.08
(2 H, m, CH2CH CH), 5.77 (1 H, d, J 7.7, CH CHCO2), 4.19 (2 H,
q, J 7.1, OCH2CH3), 2.16 (2 H, m, CH2CH2CH), 1.4–1.1 (21 H, m,
9 CH2, CH3), 0.88 (3 H, t, J 6.3, CH3). δC (50 MHz) 180.3, 144.9,
144.5, 128.3, 119.1, 59.9, 32.9, 31.8, 29.6, 29.5 (3 C), 29.3 (2 C), 28.6,
22.6, 14.2, 14.1. IR (film)/cm−1 1716, 1642, 1615. LRMS (EI) m/z 280
(M, 16%), 251 ([M − CH2CH3], 1), 125 (100). HRMS (EI) calc. for
C18H32O2 280.2402, found 280.2401.
15 min. This solution was subsequently added dropwise through a can-
nula (cannula precooled in a dry-ice jacket) to a stirring solution of
cyclic sulfites (9) (0.1 M, 1.44 mL, 0.144 mmol) in THF at −78◦C.
The mixture was stirred for 30 min and then quenched with aqueous
ammonium chloride solution (sat., 2 mL) and extracted into diethyl
ether (3 × 10 mL). The combined organic extracts were washed with
brine (20 mL), dried, and concentrated. Purification by flash chromato-
graphy (25% ethyl acetate/hexane) afforded diene (7) (6 mg, 15%) and
(2S,3E,5S)-2-butyl-5-hydroxyhexadec-3-enoic acid, ethyl ester (10) as
a yellow oil (40 mg, 78%). [α]D −34 (c 2.8, EtOH). RF 0.25 (15%
ethyl acetate/hexane). δH (200 MHz) 5.71–5.48 (2 H, m, CH CH),
4.12 (2 H, q, J 7.1, OCH2), 4.08–4.02 (1 H, m, CH(OH)), 2.95 (1 H,
q, J 7.3, CHCO2), 1.87–1.21 (30 H, m, 13 CH2, CH3, OH), 0.91–0.84
(6 H, m, 2 CH3). δC (50 MHz) 174.3, 135.8, 128.6, 72.4, 60.3, 48.7,
36.9, 32.5, 31.8, 29.5 (5C), 29.2, 29.1, 25.3, 22.5, 22.2, 14.0, 13.9, 13.7.
IR (film)/cm−1 3446, 1735. LRMS (EI) m/z 354 (M, 1.5%), 336 ([M −
C2H6], 8), 29 (100). HRMS (EI) calc. for C22H42O3 354.3133, found
354.3149.
(2E,4S,5S)-4,5-Dihydroxyhexadec-2-enoic Acid, Ethyl Ester (8)[51]
To a stirring mixture of tert-butanol (30.0 mL) and water (30.0 mL) was
added AD-mix-α (8.56 g, 1.6 g per mmol diene) and methanesulfon-
amide (0.560 g, 5.89 mmol). The resulting suspension was stirred vigor-
ously at room temperature until all solids had dissolved and both phases
were clear (organic layer yellow, aqueous layer orange). The mixture
was cooled to 0◦C and an orange precipitate formed. Ester (7) (1.50 g,
5.35 mmol) was added and the reaction was stirred vigorously at 0◦C for
32 h. The reaction was quenched with sodium sulfite (9.00 g), warmed
to room temperature and stirred for 1 h. The mixture was extracted with
ethyl acetate (3 × 30 mL), the combined organic extracts washed with
aqueous potassium hydroxide solution (2 M, 50 mL), dried, filtered, and
concentrated to afford a white solid. Purification by flash chromato-
graphy (25% ethyl acetate/hexane) afforded diol (8) as an amorphous
white solid (0.939 g, 56%, mp 77–79◦C). [α]D −27 (c 1.03, EtOH). RF
0.32 (25% ethyl acetate/hexane). δH (200 MHz) 6.92 (1 H, dd, J 15.6,
4.9, CH CHCO2), 6.13 (1 H, dd, J 15.6, 1.5, CH CHCO2), 4.21
(2 H, q, J 7.1, OCH2), 4.15–4.05 (1 H, m, obscured, CH(OH)CH CH),
3.58–3.54 (1 H, m, broad, CH2CH(OH)), 2.92 (1 H, d, J 5.3, exchanges
with D2O, CH(OH)CH CH), 2.54 (1 H, d, J 4.5, exchanges with D2O,
CH2CH(OH)), 1.52–1.25 (23 H, m, 10 CH2, CH3), 0.88 (3 H, t, J 6.2,
CH3). δC (50 MHz) 166.5, 147.2, 122.1, 74.1, 74.0, 60.6, 33.0, 31.8,
29.6 (5 C), 29.3, 25.6, 22.6, 14.1, 14.0. IR (film)/cm−1 3237, 1707,
1664. LRMS (EI) m/z 315 ([M + H], 2.5%), 297 ([M − OH], 20), 130
(100). HRMS (EI) calc. for C18H35O4 315.2535, found 315.2537.
(R)-MTPA Ester Derivative of (10)
To
a stirring solution of ester (10) (9.5 mg, 0.027 mmol) in
dichloromethane (0.5 mL) was added (R)-α-methoxy-α-(trifluoro-
methyl)phenylacetic acid (7.5 mg, 0.032 mmol), followed by a dicyclo-
hexyl carbodiimide (DCC)/4-dimethylaminopyridine (DMAP) (25 µL,
0.23 M DMAP, 2 M DCC) solution in dichloromethane. After 1 min
a white precipitate was observed and the reaction mixture was soni-
cated for 2.5 h. After this time the reaction mixture was diluted with
dichloromethane (10 mL), filtered through a short plug of celite, and
concentrated. Purification by flash chromatography afforded pure (R)-
MTPA ester as a white solid (13 mg, 86%). RF 0.50 (15% ethyl
acetate/hexane). δH (400 MHz) 7.50−7.48 (2 H, m, Ar-H), 7.40−7.37
(3 H, m, Ar-H), 5.75 (1 H, dd, J 14.5, 8.7, HC CHCH(C4H9)),
5.38 (1 H, m, obscured, CH CHCH(C4H9)), 5.35 (1 H, m, obscured,
CH2CH(O)), 4.12 (2 H, q, J 7.1, OCH2CH3), 3.55 (3 H, s, OCH3),
2.93 (1 H, q, CH(C4H9)CO2Et), 1.75−1.20 (29 H, m, 13 CH2, CH3),
0.89–0.86 (6 H, m, 2 CH3).
(2E)-3-([2R,4S,5S]-2-Oxo-5-undecyl-1,3,2- dioxathiolan-4-yl)-
propenoic Acid, Ethyl Ester
and (2E)-3-([2S,4S,5S]-2-oxo-5-undecyl-1,3,2-dioxathiolan-4- yl)-
propenoic Acid, Ethyl Ester (9)
(S)-MTPA Ester Derivative of (10)
To
dichloromethane (0.5 mL) was added (S)-α-methoxy-α-(trifluoro-
methyl)phenylacetic acid (6.0 mg, 0.026 mmol), followed by
a stirring solution of ester (10) (7.5 mg, 0.022 mmol) in
a
To a stirring solution of (8) (0.273 g, 0.868 mmol) in carbon tetrachloride
(20 mL) was added thionyl chloride (129 µL, 1.77 mmol). The resul-
tant mixture was heated at reflux for 3 h, then concentrated to yield
a clear yellow oil. Purification by flash chromatography (15% ethyl
acetate/hexane) afforded cyclic sulfites (9) as an inseparable mixture
of diastereomers in a 2 : 1 ratio (major diastereomer not identified) as
a clear, colourless oil (0.292 g, 93%). [α]D −63 (c 1.40, EtOH). RF
0.32 (10% ethyl acetate/hexane). δH (400 MHz) Major: 6.93 (1 H, dd, J
15.6, 6.4, CH CHCO2), 6.23–6.22 (1 H, m, CH CHCO2), 4.57–4.53
(1 H, m, CH(OS)CH), 4.26–4.16 (1 H, m, CH2CH(OS)), 4.23 (2 H, q,
J 7.1, OCH2), 1.78–1.26 (23 H, m, 10 CH2, CH3), 0.88 (3 H, t, J 6.7,
CH3); Minor: 6.81 (1 H, dd, J 15.6, 6.3, CH CHCO2), 6.19–6.18 (1 H,
m, CH CHCO2), 5.14–5.10 (1 H, m, CH(OS)CH), 4.72–4.67 (1 H, m,
CH2CH(OS)), 4.23 (2 H, q, J 7.1, OCH2), 1.78–1.26 (23 H, m, 10 CH2,
CH3), 0.88 (3 H, t, J 6.7, CH3). δC (50 MHz) Major: 164.9, 140.1, 125.9,
85.3, 82.9, 60.9, 30.6, 31.8, 29.4 (2C), 29.3, 29.2 (2C), 29.1, 25.7, 25.5,
22.5, 14.0; Minor: 164.9, 138.1, 125.8, 87.5, 81.2, 60.9, 32.7, 31.8,
29.4 (2C), 29.3, 29.2 (2C), 29.1, 25.7, 25.5, 22.5, 14.0. IR (film)/cm−1
1726, 1663, 1465, 1273. LRMS (+ESI) m/z 383.27 ([M + Na]). HRMS
(+ESI) calc. for C18H32O5SNa 383.1868, found 383.1868.
DCC/DMAP (19 µL, 0.23 M DMAP, 2 M DCC) solution in
dichloromethane. After 1 min a white precipitate was observed and the
reaction mixture was sonicated for 2.5 h. After this time the reaction
mixture was diluted with dichloromethane (10 mL), filtered through
a short plug of celite, and concentrated. Purification by flash chro-
matography afforded pure (S)-MTPA ester as a white solid (10 mg,
88%). RF 0.50 (15% ethyl acetate/hexane). δH (400 MHz) 7.52–7.50
(2 H, m, Ar-H), 7.40–7.36 (3 H, m, Ar-H), 5.83 (1 H, dd, J 15.4, 8.7,
HC CHCH(C4H9)), 5.57 (1 H, dd, J 15.7, 8.4, CH CHCH(C4H9)),
5.45 (1 H, q, J 6.5, CH2CH(O)), 4.11 (2 H, q, J 7.1, OCH2CH3), 3.53
(3 H, s, OCH3), 2.97 (1 H, q, J 8.0, CH(C4H9)), 1.80–1.20 (29 H, m,
13 CH2, CH3), 0.90–0.86 (6 H, m, 2 CH3).
(2E,4E)-Hexadecadienoic Acid, Methyl Ester (11)[38]
To stirring (2E)-4-(diethoxyphosphinyl)butenoic acid, methyl ester[52]
(8.70 g, 0.0368 mol) was added 4 Å molecular sieves (45 g) and dried
lithium hydroxide (0.868 g, 0.0362 mol). The mixture was placed under
nitrogen and a solution of dodecanal (5.67 g, 0.0308 mol) in THF
(200 mL) was added. The mixture was heated at reflux for 40 h,
cooled to room temperature and filtered through a 2 cm plug of silica,
washing with dichloromethane (50 mL), then diethyl ether (50 mL).
The combined washings were concentrated to afford a bright yellow
oil. Purification by flash chromatography (10% ethyl acetate/hexane)
afforded ester (11) (5.56 g, 68%) as a colourless oil. RF 0.52 (25% ethyl
acetate/hexane). δH (200 MHz) 7.33–7.20 (1 H, m, CH CHCO2),
6.17–6.11 (2 H, m, CH2CH CH), 5.78 (1 H, d, J 15.6, CH CHCO2),
3.73 (3 H, s, OCH3), 2.15 (2 H, m, CH2CH CH), 1.42–1.25 (18 H, m,
9 CH2), 0.88 (3 H, t, J 6.4, CH3CH2). δC (50 MHz) 167.8, 145.5, 145.0,
(2S,3E,5S)-2-Butyl-5-hydroxyhexadec-3-enoic Acid, Ethyl Ester (10)
To a stirring suspension of copper(i) cyanide (41.3 mg, 0.461 mmol)
in THF (4.00 mL) under nitrogen at −78◦C was added n-butyllithium
in hexanes (1.60 M, 0.560 mL, 0.896 mmol). The mixture was warmed
to room temperature and stirred for 15 min The clear yellow solution
was returned to −78◦C and boron trifluoride diethyl etherate (58.4 µL,
0.461 mmol) was added. The mixture was then stirred at −78◦C for

800
J. A. Bodkin, E. J. Humphries and M. D. McLeod
128.5, 118.9, 51.5, 33.2, 32.1, 29.8 (3 C), 29.6 (2 C), 29.4, 28.9, 22.9,
14.3. IR (film)/cm−1 1702, 1641, 1614. LRMS (EI) m/z 266 (M, 13%),
235 ([M − OCH4], 13), 111 (100). HRMS (EI) calc. for C17H30O2
266.2246, found 266.2246.
ether (3 × 30 mL). The combined ether extracts were washed with brine
(40 mL), dried, filtered, and concentrated to afford a yellow oil. Purifi-
cation by flash chromatography (10% ethyl acetate/hexane, then 50%
ethyl acetate/hexane) afforded pure ester (14) as a yellow oil (0.577 g,
90%). [α]D +30 (c 1.9, EtOH) . RF 0.09 (10% ethyl acetate/hexane).
δH (200 MHz) 5.59 (2 H, m, CH CH), 4.11 (1 H, m, CH(OH)), 3.68
(3 H, s, OCH3), 2.99 (1 H, dt, J 7.3, 7.4, CHCO2), 1.80–1.05 (31 H, m,
15 CH2, OH), 0.87 (6 H, m, 2 CH3). δC (50 MHz) 175.0, 136.1, 129.1,
73.0, 52.0, 49.1, 37.4, 32.8, 32.2, 31.9, 29.9 (5C), 29.6, 29.2, 27.3, 25.7,
22.9, 22.8, 14.4, 14.3. IR (film)/cm−1 3362, 1740. LRMS (EI) m/z 368
(M, 1.0%), 309 ([M − CO2CH3], 8.5), 181 (100). HRMS (EI) calc. for
C23H44O3 368.3290, found 368.3295.
(2E,4S,5S)-4,5-Dihydroxyhexadec-2-enoic Acid, Methyl Ester (12)
To a stirring mixture of tert-butanol (35 mL) and water (35 mL) was
added AD-mix-α (10.5 g, 1.4 g per mmol diene) and methanesul-
fonamide (0.785 g, 8.25 mmol). The resulting suspension was stirred
vigorously at room temperature until all solid dissolved and both
phases were clear (organic layer yellow, aqueous layer orange), at which
time it was cooled to 0◦C to effect precipitation of an orange solid.
Ester (11) (2.00 g, 7.51 mmol) was added and the mixture stirred at
0◦C for 18 h before the reaction was quenched with sodium sulfite
(11.3 g), warmed to room temperature and stirred for 1 h. The mix-
ture was extracted into dichloromethane (3 × 50 mL). The combined
organic extracts were washed with aqueous potassium hydroxide solu-
tion (2 M, 70 mL), dried, filtered, and concentrated to afford a white
solid. Purification by flash chromatography (25% ethyl acetate/hexane)
afforded diol (12) as a white solid (1.66 g, 74%, mp 65–69◦C). [α]D
−36 (c 1.8, EtOH) . RF 0.10 (25% ethyl acetate/hexane). δH (200 MHz)
6.95 (1 H, dd, J 15.5, 5.0, CH CHCO2), 6.14 (1 H, dd, J 15.7, 1.6,
CH CHCO2), 4.16–4.11 (1 H, m, CH(OH)CH CH), 3.76 (3 H, s,
OCH3), 3.55–3.50 (1 H, m, CH2CH(OH), 2.43 (1 H, d, J5.3, exchanges
with D2O, CH(OH)CH CH), 1.98 (1 H, d, J4.7, exchanges with
D2O, CH2CH(OH), 1.65–1.20 (20 H, m, 10 CH2), 0.88 (3 H, t, J 6.4,
CH3CH2). δC (50 MHz) 167.1, 147.7, 122.1, 74.3 (2C), 52.0, 33.4, 33.2,
29.9 (5C), 29.6, 25.9, 22.9, 14.4. IR (film)/cm−1 3281, 1714, 1666.
LRMS (+ESI) m/z 323 ([M + Na], 100%).
(2S,3E,5S)-2-hexyl-5-(tert-butyldimethylsilyloxy)hexadec-
3-enoic Acid, Methyl Ester (16)
To a stirring solution of (14) (0.201 g, 0.545 mmol) in dimethylfor-
mamide (0.5 mL) was added imidazole (0.190 g, 2.79 mmol) and tert-
butyldimethyl chlorosilane (0.283 g, 1.88 mmol). The resulting solution
was stirred at room temperature for 90 h before quenching with aque-
ous sodium hydrogencarbonate solution (sat., 2 mL) and extracting with
ethyl acetate (3 × 10 mL). The combined organic extracts were washed
with brine (10 mL), dried, filtered and concentrated to afford a mixture
of white solid and clear oil. Purification by flash chromatography (4%
diethyl ether/hexane) afforded pure ester (16) as a clear oil (0.235 g,
89%). [α]D +17 (c 1.9, EtOH). RF 0.30 (4% diethyl ether/hexane). δH
(200 MHz) 5.49 (2 H, m, CH CH), 4.03 (1 H, m, CH(OH)), 3.66 (3 H,
s, OCH3), 2.96 (1 H, m, CHCO2), 1.74–0.84 (45 H, m, C11H23, C6H13
,
C(CH3)3), 0.097–0.00 (6 H, m, Si(CH3)2). δC (100 MHz) 174.7, 136.7,
127.6, 73.5, 63.4, 51.6, 48.9, 38.4, 33.0, 32.3, 32.0, 31.8, 29.7 (2 C),
29.6, 29.5, 29.1, 27.2, 26.1, 26.0 (2 C), 25.4, 22.8, 22.7, 18.4, 14.2,
14.1, −4.2, −4.8. IR (film)/cm−1 1742. LRMS (EI) m/z 481 ([M −
H], 0.50%), 467 ([M − CH3], 1.8), 425 (100). HRMS (EI) calc. for
C29H57O3Si 481.4077, found 481.4073.
(2E)-3-([2R,4S,5S]-2-Oxo-5-undecyl-1,3,2-dioxathiolan-4-yl)-
propenoic Acid, Methyl Ester
and (2E)-3-([2S,4S,5S]-2-oxo-5-undecyl-1,3,2-dioxathiolan-
4-yl)-propenoic Acid, Methyl Ester (13)[53]
(2S,3E,5S)-2-Hexyl-5-(tert-butyldimethylsilyloxy)
hexadec-3-enoic Acid
and (2R,3E,5S)-2-Hexyl-5-(tert-butyldimethylsilyloxy)
hexadec-3-enoic Acid (17)
To a stirring solution of (12) (6.97 g, 0.0232 mol) in carbon tetrachlo-
ride (400 mL) was added thionyl chloride (5.08 mL, 0.0696 mol). The
mixturewasheatedatrefluxfor4 hbeforeallowingittocoolandconcen-
trating to afford a yellow oil. Purification by flash chromatography (8%
ethyl acetate/hexane) afforded cyclic sulfites (13), which was an insep-
arable mixture of diastereomers, as a colourless oil (7.38 g, 92%). [α]D
−72 (c 1.8, EtOH). RF 0.25 (10% ethyl acetate/hexane). δH (200 MHz)
Major: 6.95 (1 H, dd, J 15.6, 6.5, CH CHCO2), 6.22 (1 H, d, J 15.6,
CH CHCO2), 4.60−4.52 (1 H, m, CH(OS)CH), 4.22−4.13 (1 H, m,
CH2CH(OS)), 3.78 (3 H, s, OCH3), 1.87−1.26 (20 H, m, 10 CH2), 0.88
(3 H, t, J 6.4, CH3); Minor: 6.84 (1 H, dd, J 15.6, 6.19, CH CHCO2),
6.22 (1 H, d, J 15.6, CH CHCO2), 5.16−5.09 (1 H, m, CH(OS)CH),
4.75−4.65 (1 H, m, CH2CH(OS)), 3.79 (3 H, s, OCH3), 1.87−1.26
(20 H, m, 10 CH2), 0.88 (3 H, t, J 6.4, CH3CH2). δC (50 MHz) Major:
165.4, 140.8, 125.7, 85.5, 81.4, 52.2, 32.0, 29.8 (2 C), 29.6, 29.5 (2C),
29.4, 26.0, 25.8, 22.9, 14.3; Minor: 165.4, 138.7, 125.5, 87.9, 83.2,
52.1, 33.0, 30.9, 29.8, 29.6, 29.5 (2 C), 29.4, 26.0, 25.8, 22.9, 14.3. IR
(film)/cm−1 1731, 1665. LRMS (EI) m/z 347 ([M + H], 1.2%), 315
([M − OCH3], 1.8), 98 (100). HRMS (EI) calc. for C17H31O5S
347.1892, found 347.1895.
To a stirring solution of (16) (0.175 mg, 0.362 mmol) in methanol
(7 mL) was added barium hydroxide octahydrate (3.42 g, 10.8 mmol).
The resulting suspension was stirred at room temperature for 64 h before
diluting with brine (10 mL), acidifying with hydrochloric acid (1 M,
2 mL) and extracting into diethyl ether (3 × 15 mL). The residual bar-
ium hydroxide octahydrate was washed with additional ether (50 mL).
The organic extracts were combined, washed with brine (30 mL),
dried, filtered, and concentrated to afford a viscous oil. Purification
by flash chromatography (10% diethyl ether/hexane + 0.25% acetic
acid) afforded pure acids (17) as a viscous pale yellow oil (0.165 g,
97%). RF 0.03 (10% diethyl ether /hexane + 0.25% acetic acid). δH
(200 MHz) 5.54 (2 H, m, CH CH), 4.07 (1 H, m, CH(OH)), 2.98 (1 H,
m, CH(C6H13)CO2), 1.74–0.57 (46 H, m, C11H23, C6H13, C(CH3)3),
0.097–0.00 (6 H, m, Si(CH3)2). δC (75 MHz) 181.1/181.0#, 137.4,
127.1/127.0#, 73.6/73.5#, 49.0, 38.6, 32.7, 32.6, 32.3, 32.0, 30.0 (2 C),
29.7, 29.3, 29.3/29.3#, 27.3, 26.3 (3 C), 25.7, 25.6, 23.1, 22.9, 18.6,
14.5, 14.4, −3.9, −4.4. IR (film)/cm−1 1713. LRMS (EI) m/z 467 ([M
− H], 0.35%), 411 ([M − C(CH3)3], 48), 383 (100). HRMS (EI) calc.
for C28H55O3Si 467.3920, found 467.3916.
(2S,3E,5S)-2-Hexyl-5-hydroxyhexadec-3-enoic Acid, Methyl Ester (14)
To a stirring suspension of copper(i) cyanide (0.497 g, 5.55 mol) in
THF (15 mL) under nitrogen at −78◦C was added n-hexyllithium in
hexanes (2.33 M, 4.60 mL, 10.7 mmol). The mixture was warmed to
room temperature and stirred for 15 min before returning to −78◦C
for addition of boron trifluoride diethyl etherate (1.36 mL, 10.7 mmol).
The mixture was stirred at −78◦C for 15 min, and then added dropwise
through a dry-ice jacketed cannula to a stirring solution of cyclic sulfites
(13) (0.601 g, 1.73 mmol) in THF (20 mL) under nitrogen, at −78◦C.
The mixture was stirred at −78◦C for 30 min before quenching with
aqueous ammonium chloride solution (sat., 30 mL) and extracting into
(2E,4E)-Hexadecadienoic Acid (21)[54]
To a stirring solution of (11) (3.78 g, 0.0142 mol) in THF (140 mL) was
added potassium hydroxide solution (2 M, 25.3 mL, 0.0506 mol). The
mixture was heated at reflux for 22 h before allowing to cool, acidi-
fying with hydrochloric acid (1 M, to pH 2) and extracting into ethyl
acetate (3 × 40 mL). The combined organic layers were dried, filtered,
and concentrated. Purification by flash chromatography (15% ethyl
acetate/hexane + 0.25% acetic acid) afforded pure acid (21) as a white
# Signal pairs observed due to partial epimerization at C2 and the formation of two diastereomeric products.

The Total Synthesis of (–)-Tetrahydrolipstatin
801
solid (3.07 g, 86%, mp 53–59◦C). RF 0.20 (15% ethyl acetate/hexane +
0.25% acetic acid). δH (200 MHz) 10.5 (1 H, s (br), CO2H), 7.37–7.25
(1 H, m, CH CHCO2), 6.20–6.17 (2 H, m, CH2CH CH), 5.77 (1 H,
d, J 15.3, CH CHCO2), 2.17–2.05 (2 H, m, CH2CH CH), 1.42–0.90
(18 H, m, 9 CH2), 0.79 (3 H, t, J 6.2, CH3). δC (50 MHz) 173.1, 147.7,
146.4, 128.3, 118.4, 33.2, 32.0, 29.7 (3 H), 29.5, 29.4, 29.3, 28.7, 22.8,
14.2. IR (Nujol)/cm−1 1709, 1636. LRMS (EI) m/z 252 (M, 20%), 235
([M − OH], 7), 57 (100). HRMS (EI) calc. for C16H28O2 252.2089,
found 252.2086.
mixture was heated at reflux for 22 h before allowing it to cool and con-
centrating to afford a yellow oil. Purification by flash chromatography
(5% ethyl acetate/hexane) afforded cyclic sulfites (23) as an insepara-
ble mixture of diastereomers, as a pale yellow oil (2.70 g, 92%). RF
0.27 (5% ethyl acetate/hexane). δH (200 MHz) Major: 7.09 (1 H, dd,
J15.4, 5.8, CH CHCO2), 6.38 (1 H, m, CH CHCO2), 4.83 (2 H,
s, CH2CCl3), 4.79–4.57 (2 H, m, CH(OS)CH CH, CH2CH(OS)),
1.81–1.25 (20 H, m, 10 CH2), 0.88 (3 H, m, CH3); Minor: 6.97 (1 H,
dd, J15.8, 5.9, CH CHCO2), 6.30 (1 H, m, CH=CHCO2), 5.18 (1 H,
m, CH(OS)CH CH), 4.83 (2 H, s, CH2CCl3), 4.23 (1 H, dd, J 8.2,
4.7, CH2CH(OS)); 1.81–1.25 (20 H, m, 10 CH2), 0.88 (3 H, m, CH3).
δC (50 MHz) Major: 163.5, 142.8, 124.1, 85.1, 83.2, 74.3, 32.0, 31.0,
29.7 (2C), 29.5, 29.4 (2C), 29.3, 25.9, 25.7, 22.8, 14.2; Minor 163.5,
141.0, 123.8, 94.7, 87.8, 81.2, 32.0, 31.0, 29.7 (2C), 29.5, 29.4 (2C),
29.3, 25.9, 25.7, 22.8, 14.2. IR (film)/cm−1 1742, 1664, 1465. LRMS
(EI) m/z 399 ([M − SO2], 0.05%), 382 ([M − HSO3], 0.3), 315 ([M −
OCH2CCl3], 3.3), 83 (100%). HRMS (EI) calc. for C18H28O337Cl35Cl2
399.1075, found 399.1082; calc. for C18H28O335Cl3 397.1104, found
397.1102.
(2E,4E)-Hexadecadienoic Acid, 2,2,2-Trichloroethyl Ester (18)
Acid (21) (3.07 g, 0.0122 mol) was dissolved in dichloromethane
(50 mL) by sonication and then cooled to 0◦C. Dimethylformamide
(3 drops) and oxalyl chloride (1.06 mL, 0.0122 mol) were added. The
mixture was allowed to warm to room temperature and stirred for
50 min before it was added by means of a cannula to a stirring solution
of trichloroethanol (1.29 mL, 0.0134 mol), triethylamine (3.40 mL,
0.0244 mol) and 4-(dimethylamino)pyridine (1.51 g, 0.0124 mol). The
mixture stirred at room temperature for 20 h before quenching with
aqueous sodium hydrogencarbonate solution (sat., 20 mL) and extract-
ing into diethyl ether (3 × 25 mL). Purification by flash chromatography
(2% diethyl ether/hexane) afforded pure ester (18) as a colourless
oil (4.41 g, 94%). RF 0.40 (5% diethyl ether/hexane). δH (200 MHz)
7.43–7.30 (1 H, m, CH CHCO2), 6.25–6.10 (2 H, m, CH2CH CH),
5.83 (1 H, d, J 15.4, CH CHCO2), 4.78 (2 H, s, CH2CCl3), 2.45–2.30
(2 H, m, CH2CH CH), 1.66–0.98 (18 H, m, 9 CH2), 0.86 (3 H, t, J 5.5,
CH3). δC (50 MHz) 165.5, 147.6, 146.8, 128.2, 117.2, 95.3, 74.0, 33.2,
32.0, 29.8, 29.7 (2 C), 29.5, 29.4, 29.3, 28.7, 22.8, 14.2. IR (film)/cm−1
1733, 1641, 1616. LRMS (EI) m/z 384 (C18H29O237Cl35Cl2, 13%),
382 (C18H29O235Cl3, 13), 347 (C18H29O235Cl2, 24), 81 (100). HRMS
(EI) calc. for C18H29O237Cl35Cl2 384.1203, found 384.1206; calc. for
C18H29O235Cl3 382.1233, found 382.1234.
(2S,3E,5S)-2-Hexyl-5-hydroxyhexadec-3-enoic Acid,
2,2,2-Trichloroethyl Ester (19)
To a stirring suspension of copper(i) cyanide (1.69 g, 0.0189 mol)
in THF (50 mL) under a nitrogen atmosphere at −78◦C was added
n-hexyllithium in hexanes (2.08 M, 17.4 mL, 0.0362 mol). The mixture
was warmed to room temperature and stirred for 15 min before return-
ing to −78◦C for addition of boron trifluoride diethyl etherate (4.58 mL,
0.0361 mol). The mixture was stirred at −78◦C for 20 min, then added
dropwise by means of a cannula (cannula pre-cooled to −78◦C) over
15 minutes to a stirring solution of (23) (2.64 g, 5.70 mmol) in THF
(60 mL) maintained under a nitrogen atmosphere at −78◦C. The mix-
ture was stirred at −78◦C for 60 min before quenching with aqueous
ammonium chloride solution (sat., 80 mL) and extracting into diethyl
ether (3 × 80 mL). The combined ether extracts were dried, filtered, and
concentrated to afford a yellow oil and purple solid. Purification by flash
chromatography (5% ethyl acetate/hexane) afforded pure ester (19) as
a pale yellow oil (2.34 g, 84%). [α]D +22 (c 1.8, EtOH). RF 0.46 (15%
ethyl acetate/hexane). δH (200 MHz) 5.68–5.57 (2 H, m, CH CH),
4.74 (2 H, s, CH2CCl3), 4.13–4.04 (1 H, m, CH(OH)), 3.19–3.09 (1 H,
m, CHCO2), 1.85–1.20 (31 H, m, 15 CH2, OH) 0.87 (6 H, t, J 6.3, 2
CH3). δC (50 MHz) 172.6, 136.7, 127.8, 74.0, 72.6, 48.6, 37.2, 32.3,
32.0, 31.7, 29.7 (5C), 29.4, 29.0, 27.0, 25.8, 25.4, 22.7, 22.6, 14.2, 14.1.
IR (film)/cm−1 3352, 1746. LRMS (EI) m/z 486 (C24H43O337Cl35Cl2,
0.5%), 484 (C24H43O335Cl3, 0.5), 469 (C24H42O237Cl35Cl2, 0.6), 467
(C24H42O235Cl3, 0.7), 449 (C24H43O335Cl2, 5.6), 181 (100). HRMS
(EI): calc. for C24H43O337Cl35Cl2 486.2248, found 486.2250; calc. for
C24H43O335Cl3 484.2278, found 484.2279.
(2E,4S,5S)-4,5-Dihydroxyhexadec-2-enoic Acid,
2,2,2-Trichloroethyl Ester (22)
To a stirring mixture of tert-butanol (50 mL) and water (50 mL)
was added AD-mix-α (16.4 g, 1.6 g per mmol diene), methanesulfon-
amide (1.04 g, 0.0109 mol), and sodium hydrogencarbonate (2.75 g,
0.0327 mol). The resulting suspension was stirred vigorously at room
temperature until all solid dissolved, at which time it was cooled
to 0◦C to effect precipitation of an orange solid. Ester (18) (4.00 g,
0.0104 mol) was added, washing with tert-butanol (2 mL). The mix-
ture was stirred at 0◦C for 25 h before the reaction was quenched
with sodium sulfite (22.5 g) and stirred at room temperature for
30 min. Water (50 mL) was added and the mixture extracted with
ethyl acetate (3 × 30 mL). The combined organic extracts were washed
with brine, dried, filtered, and concentrated to afford a white sludge.
Purification by flash chromatography (30% diethyl ether/hexane)
afforded pure diol (22) as a white solid (2.64 g, 61%, mp 47–48◦C).
[α]D −37 (c 1.8, EtOH) . RF 0.05 (30% diethyl ether/hexane). δH
(200 MHz) 7.08 (1 H, dd, J 15.6, 4.6, CH CHCO2), 6.22 (1 H,
d, J 15.6, CH CHCO2), 4.77 (2 H, s, CH2CCl3), 4.14 (1 H, m,
CH(OH)CH CH), 3.52 (1 H, m, CH2CH(OH)), 3.33 (2 H, s (br),
2 OH), 1.49–1.23 (20 H, m, 10 CH2), 0.85 (3 H, t, J 5.8, CH3).
δC (50 MHz) 164.7, 149.9, 120.5, 94.9, 74.1, 33.2, 31.9, 29.7, 29.6
(6C), 29.4, 25.7, 22.7, 14.1. IR (film)/cm−1 3374, 1723, 1654. LRMS
(EI) m/z 401 (C18H30O337Cl35Cl2, 0.07%), 399 (C18H30O335Cl3,
0.08), 384 (C18H29O237Cl35Cl2, 1.4), 382 (C18H29O235Cl3, 1.4), 231
(100). HRMS (EI) calc. for C18H30O337Cl35Cl2 401.1231, found
401.1224; calc. for C18H30O335Cl3 399.1261, found 399.1253; calc.
for C18H29O235Cl3 382.1233, found 382.1232.
(2S,3E,5S)-2-Hexyl-5-hydroxyhexadec-3-enoic Acid (4)
ProcedureA: 2,2,2-Tricloroethylester cleavage performed with zinc and
acetic acid. To a stirring solution of (19) (1.81 g, 3.72 mmol) in acetic
acid (120 mL) was added zinc powder (6.28 g, 0.0961 mol). The grey
suspension was stirred at room temperature for 4 h before diluting with
ethyl acetate (100 mL) and filtering through a 3 cm plug of celite, wash-
ing with ethyl acetate (200 mL). Following concentration, the filtrate
was extracted with ethyl acetate (3 × 20 mL), dried, filtered, and concen-
trated. Purification by flash chromatography (20% ethyl acetate/hexane
+ 0.1% acetic acid) afforded pure acid (4) as a white solid (0.976 g,
74%, mp 70–74◦C). [α]D +31 (c 1.7, EtOH). RF 0.06 (20% ethyl
acetate/hexane + 0.1% acetic acid). δH (200 MHz) 5.63–5.59 (2 H, m,
CH CH), 5.02 (2 H, s (b), OH, CO2H), 4.09 (1 H, m, CH(OH)), 3.01
(1 H, m, CHCO2), 1.79–1.25 (30 H, m, 15 CH2), 0.88 (6 H, m, 2 CH3).
δC (50 MHz) 179.3, 137.0, 129.1, 73.4, 49.1, 37.8, 33.0, 32.6, 32.3, 30.3
(5 C), 30.0, 29.6, 27.7, 26.1, 23.4, 23.3, 14.8 (2 C). IR (film)/cm−1 3242,
1684 cm−1. LRMS (EI) m/z 353 ([M − H], 100%). HRMS (−ESI) calc.
for C22H41O3 353.3056, found 353.3056.
(2E)-3-([2R,4S,5S]-2-Oxo-5-undecyl-1,3,2- dioxathiolan-4-yl)-
propenoic Acid, 2,2,2-Trichloroethyl Ester
and (2E)-3-([2S,4S,5S]-2-oxo-5-undecyl-1,3,2-dioxathiolan-
4- yl)-propenoic Acid, 2,2,2-Trichloroethyl Ester (23)
To a stirring solution of (22) (2.64 g, 6.32 mmol) in carbon tetrachlo-
ride (120 mL) was added thionyl chloride (1.40 mL, 0.0192 mol). The
Procedure B: Methyl ester hydrolysis performed with potassium
trimethylsilanoate.To a stirring solution of (14) (20.8 mg, 0.0564 mmol)

802
J. A. Bodkin, E. J. Humphries and M. D. McLeod
in THF (0.5 mL) was added potassium trimethylsilanoate (13.9 g,
0.108 mmol). The resulting solution was stirred at room temperature
for 25 h before quenching with aqueous ammonium chloride solu-
tion (sat., 5 mL), acidifying with hydrochloric acid (1 M, 0.5 mL) and
extracting into ethyl acetate (3 × 10 mL).The combined organic extracts
were washed with brine (15 mL), dried, filtered, and concentrated to
afford a pale yellow solid. Purification by flash chromatography (40%
ethyl acetate/hexane + 0.25% acetic acid) afforded (4) as a white solid
(3.2 mg, 16%).
N-[(Phenylmethoxy)carbonyl]-L-leucine (1S)-1-[[(2S,3S)-
3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl Ester (20)[9]
To
a stirring solution of N-carbobenzyloxy-l-leucine (93.6 mg,
0.353 mmol) at 0◦C in dichloromethane (0.9 mL) was added 1,3-
dicyclohexylcarbodiimide (43.1 mg, 0.209 mmol). The mixture was
stirred for 15 min, concentrated, and dissolved in dimethylformamide
(0.7 mL). The resulting solution was added to a stirring mixture of
(3S,4S)-3-hexyl-4-[(2S)-2-hydroxytridecyl]-2-oxetanone (2) (30.8 mg,
0.0869 mmol) and 4-(dimethylamino)pyridine (4.56 mg, 0.0373 mmol)
in dimethylformamide (0.45 mL), washing with dimethylformamide
(0.05 mL). The solution was stirred at room temperature for 80 min
before diluting with water (5 mL) and extracting into diethyl
ether (3 × 5 mL). Purification by flash chromatography (8% ethyl
acetate/hexane) afforded pure N-[(phenylmethoxy)carbonyl]-l-leucine
(1S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester (20)
as a colourless oil (45.4 mg, 87%). [α]D −23 (c 1.1, CHCl3) (lit.[9]
[α]D −23.86 (c 1.06, CHCl3)). RF 0.13 (10% ethyl acetate/hexane). δH
(200 MHz) 7.35 (5 H, m, 5 Ar-H), 5.11 (2 H, s, CH2Ph), 5.00 (2 H, m,
NH, C11H23CH(OCO)), 4.37 (2 H, m, CH2CHOCO, CH(NH)), 3.20
(1 H, m, CH(C6H13), 2.16–1.26 (35 H, m, 17 CH2, OH), 0.96 (6 H, d,
J 6.3, CH(CH3)2), 0.89 (6 H, m, 2 CH3). δC (50 MHz) 172.9, 171.6,
156.6, 136.9, 128.9 (2 C), 128.6 (2 C), 128.5, 75.0, 72.7, 67.4, 57.4, 53.2,
42.0, 39.1, 34.5, 32.3, 31.9, 30.3, 30.2, 30.1, 30.0, 29.8, 29.7, 29.4, 28.0,
27.1, 25.5, 25.2, 23.3, 23.1, 22.9, 22.1, 14.5, 14.4. IR (film)/cm−1 3354,
1824, 1724. LRMS (EI) m/z 601 (M, 13%), 91 (100). HRMS (EI) calc.
for C36H59NO6 601.4342, found 601.4350.
(3S,4R)-3-hexyl-4-[(1S,2S)-1-bromo-2-hydroxytridecyl]-
2-oxetanone (trans-(3))
and (3S,4S)-3-hexyl-4-[(1R,2S)-1-bromo-2-hydroxytridecyl]-
2-oxetanone (cis-(3))
Procedure A: Bromolactonization performed in methanol cosolvent. To
a stirring solution of (4) (0.207 g, 0.584 mmol) in methanol (11 mL) and
aqueous sodium hydrogen carbonate solution (sat., 11 mL) at room tem-
perature was added bromine solution in carbon tetrachloride (0.298 M,
5.68 mL, 1.69 mmol). The resulting mixture was stirred at room tem-
perature for 20 s before diluting with water (15 mL), extracting with
dichloromethane (3 × 20 mL), drying, and concentrating to afford a 6 : 1
mixture of bromolactones trans-(3) and cis-(3) (0.238 g) as an oily solid.
Purificationbyflashchromatography(10%diethylether/hexane +0.1%
triethylamine) affordedpure trans-(3) asacolourless oil (32.9 mg, 13%).
[α]D −14 (c 2.0, EtOH). RF 0.02 (10% diethyl ether/hexane + 0.1% tri-
ethylamine). δH (400 MHz) 4.47 (1 H, dd, J 8.9, 3.9, CH(Br)CHOCO),
4.21 (1 H, dd, J 8.9, 3.5, CH(Br)), 3.92 (1 H, m, CH(OH)), 3.53 (1 H,
dt, J 7.4, 3.9, CH(C6H13)), 2.1–1.2 (31 H, m, 15 CH2, OH), 0.91–0.83
(6 H, m, 2 CH3). δC (100 MHz) 170.8, 74.9, 73.7, 60.2, 58.7, 34.4, 32.5,
32.2, 30.3, 30.2 (2 C), 30.1, 30.0 (3 C), 28.5, 27.2, 26.5, 23.4, 23.2, 14.8,
14.7. IR (film)/cm−1 3480, 1828. LRMS (EI) m/z 435 ([M + 81Br],
14%), 433 ([M + 79Br], 17), 417 ([M + 81Br − OH], 25), 415 ([M
(S)-N-Formylleucine (1S)-1-[[(2S,3S)-3-Hexyl-4-oxo-
2-oxetanyl]methyl]dodecyl Ester [(–)-Tetrahydrolipstatin] (1)[5]
To a stirring solution of (20) (10.4 mg, 0.0173 mmol) in tetrahydrofuran
(0.9 mL) was added 10% palladium on charcoal (10.0 mg). The result-
ing mixture was stirred at room temperature under hydrogen for 3 h
before filtering through celite, washing with tetrahydrofuran (2 mL),
and concentrating. The residue was then redissolved in diethyl ether
(0.1 mL) and formic acetic anhydride[55] (0.025 mL) was added. The
solution was stirred at room temperature for 20 min before diluting
with water (4 mL) and extracting into diethyl ether (3 × 4 mL). Purifi-
cation by flash chromatography (20% ethyl acetate/hexane) afforded
pure tetrahydrolipstatin (1) (6.5 mg, 76%, mp 36–38◦C). [α]D −32
(c 1.8, CHCl3)) (lit.[2] [α]D −32 (c 1, CHCl3)). RF 0.14 (20% ethyl
acetate/hexane). δH (400 MHz) 8.22 (1 H, s, CHO), 5.91 (1 H, d,
J 8.2, NH), 5.03(1 H, m, CH(O-Leucine)), 4.69(1 H, m, CH(NH)), 4.28
(1 H, m, CH2CHOCO), 3.22 (1 H, dt, J 7.6, 3.8, CH(C6H13)), 2.21–
2.09 (1 H, m, CH(OH)CHAHBCO), 2.05 (1 H, m, CH(OH)CHAHBCO),
1.76–1.50 (12 H, m, 6 CH2), 1.35–1.25 (21 H, m, 10 CH2(CH3)2CH),
0.97 (6 H, d, J5.7 (CH3)2CH), 0.86 (6 H, m, 2 CH3). δC (100 MHz)
171.9, 170.7, 160.6, 74.7, 72.8, 57.1, 49.6, 41.6, 38.7, 34.1, 31.9, 31.5,
29.7, 29.6 (2 C), 29.5, 29.4, 29.3, 29.0, 27.6, 26.7, 25.1, 24.9, 22.9, 22.7,
22.5, 21.8, 14.1, 14.0. IR (film)/cm−1 3354, 1824, 1724. LRMS (EI)
m/z 496 ([M + H], 4.4%), 114 (100). HRMS (EI) calc. for C29H54NO5
496.4002, found 496.4007.
+
79Br − OH], 31), 309 (100). HRMS (EI) calc. for C22H41O381Br
435.2297, found 435.2293; calc. for C22H41O379Br 433.2317, found
433.2315.
Procedure B: Bromolactonization performed in dichloromethane
cosolvent. To a stirring solution of (4) (23.9 mg, 0.0674 mmol) in
dichloromethane (1.5 mL) and aqueous sodium hydrogencarbonate
solution (sat., 1.5 mL) at room temperature was added bromine solution
in carbon tetrachloride (0.298 M, 0.711 mL, 0.212 mmol). The resulting
mixture was stirred at room temperature for 5 minutes before it was
diluted with water (5 mL), extracted with dichloromethane (3 × 5 mL),
dried, and concentrated. Purification by flash chromatography (5%
diethyl ether/hexane) afforded a 2 : 1 mixture of cis-(3) and trans-(3)
as an oily solid (9.00 mg, 31%). δH (200 MHz) Major δ 4.92 (1 H, dd,
J 11, 6.1, CH(Br)CH(OCO)), 4.02 (1 H, dd, J 11, 1.6, CH(Br)), 3.75
(2 H, m, CH(OH), CH(C6H13)), 2.00–1.22 (31 H, m, 15 CH2, OH),
0.88 (6 H, m, 2 CH3). IR (film)/cm−1 3448, 1830. 1H NMR data for
the minor component of the mixture was identical to that reported for
trans-(3) above.
(3S,4S)-3-Hexyl-4-[(2S)-2-hydroxytridecyl]-2-oxetanone (2)[12]
To a stirring solution of crude bromolactones (3) (50.7 mg, 0.117 mmol)
in toluene (6 mL) at 0◦C was added di-tert-butylperoxyoxalate
(CAUTION!)[50] (2.84 mg, 0.0121 mmol) and diphenyl diselenide
(84.3 mg, 0.270 mmol, 0.045 M in reaction solvent) under a nitrogen
atmosphere. To this mixture was added tributyltin hydride (118 µL,
0.439 mmol) and the resulting solution was stirred at 0◦C for 2.5 h before
concentrating to afford a yellow oil. Purification by flash chromatogra-
phy (8% ethyl acetate/hexane) afforded pure oxetanone (2) as a white
solid (26.0 mg, 63%, mp 54–57◦C). [α]D −16 (c 1.4, CHCl3) (lit.[12]
[α]D −15.3 (c 1.2, CH2Cl2)). RF 0.14 (12% ethyl acetate/hexane).
δH (200 MHz) 4.47 (1 H, dt, J 6.5, 4.0, CH2CHOCO), 3.77 (1 H, m,
CH(OH)), 3.31 (1 H, ddd, J 8.5, 6.7, 4.0, CH(C6H13)), 2.10–1.20 (33
H, m, 16 CH2, OH), 0.91–0.83 (6 H, m, 2 CH3). δC (50 MHz) 171.6,
76.6, 72.4, 69.7, 57.2, 41.6, 38.1, 32.6, 32.3, 30.0 (2 C), 29.9 (2 C), 29.7,
29.3, 28.2, 27.2, 25.8, 23.1, 22.9, 14.5, 14.4. IR (film)/cm−1 3445, 1816.
LRMS(EI)m/z 354(M, 1.6%), 336([M−H2O], 2.0), 126(100). HRMS
(EI) calc. for C22H42O3 354.3134, found 354.3132.
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