A synthesis of the hypocholesterolemic agent 1233A via asymmetric [2 + 2] cycloaddition

Article abstract of DOI:10.1055/s-1998-2194

Key steps in a synthesis of the cholesterol biosynthesis inhibitor 1233A include: (a) asymmetric 1,4-reduction of an α,β-unsaturated ester using an enantiopure semicorrin (Pfaltz reduction); (b) a Cu(I)-mediated coupling of an iodoalkene and an alkenylstannane to generate a diene; (c) an asymmetric Lewis acid catalysed [2+2] cycloaddition of (trimethylsilyl)ketene to an aldehyde mediated by an enantiopure bis(sulfonamide) ligand.

Full text of DOI:10.1055/s-1998-2194

SYNTHESIS
November 1998
1655
A Synthesis of the Hypocholesterolemic Agent 1233A Via Asymmetric [2 + 2]
Cycloaddition
Brian W. Dymock,a Philip J. Kocienski,*a Jean-Marc Ponsb
a Department of Chemistry, Glasgow University, Glasgow, G12 8QQ, UK
b Laboratoire de Réactivité en Synthèse Organique (RéSo), UMR 6516, Centre de St. Jerôme, boite D12, F-13397 Marseille Cedex 20, France
Received 27 May 1998
Abstract: Key steps in a synthesis of the cholesterol biosynthesis
inhibitor 1233A include: (a) asymmetric 1,4-reduction of an α,β-
unsaturated ester using an enantiopure semicorrin (Pfaltz reduc-
cuprate 5 bearing a trimethylsilylmethyl group as an acti-
tion); (b) a Cu(I)-mediated coupling of an iodoalkene and an alke-
nylstannane to generate a diene; (c) an asymmetric Lewis acid
The construction of fragment 2 (Scheme 2) began with
carbocupration of ethyl but-2-ynoate with the mixed
vating, nontransferrable ligand.21 The pure (E)-alkenoate
6 (68% yield) underwent smooth catalytic asymmetric re-
duction mediated by Pfaltz’s semicorrin 722 to install the
stereogenic centre at C-7 (1233A numbering) affording 8
in 96% yield with an enantiomeric ratio of >95:5 accord-
ing to NMR analysis of the mixture using a chiral lan-
thanide shift reagent [Eu(hfc)3]. Reduction of ester 8 to
aldehyde 9 using DIBALH was followed by a Colvin
alkynylation23 using dimethyl diazophosphonate generat-
ed in situ from 1-diazo-1-(dimethoxyphosphoryl)propan-
2-one24,25 to give the alkyne 10 in excellent overall yield.
To complete the sequence, Negishi carboalumination26 of
alkyne 10 followed by iodinolysis of the intermediate alk-
enyldimethylalane gave (E)-iodoalkene 2 in 44% overall
yield (E/Z >20:1) for the 6 steps from cuprate 5.
catalysed [2+2] cycloaddition of (trimethylsilyl)ketene to an alde-
hyde mediated by an enantiopure bis(sulfonamide) ligand.
Key words: diene synthesis, coupling, [2+2] cycloaddition, β-lact-
one, chiral Lewis acid, carboxylation, Pfaltz reduction
An important milestone in the treatment of arteriosclero-
sis was the discovery that lovastatin (mevinolin) reduces
plasma levels of cholesterol by inhibiting the rate limiting
third step in the cholesterol biogenesis pathway, namely
the conversion of 3-hydroxy-3-methylglutaryl-CoA to
mevalonate catalysed by 3-hydroxy-3-methylglutaryl-
CoA reductase (HMG-CoA reductase).1,2 Subsequently, a
Merck group reported the isolation of a metabolite from
Scopulariopsis3 and Fusarium4 species which inhibited the
preceding step in cholesterogenesis, the condensation of
acetyl CoA and acetoacetyl CoA to form 3-hydroxy-3-
methylglutaryl CoA catalysed by HMG-CoA synthase.5,6
The new metabolite was identical to 1233A which had been
isolated in 1970 from a Cephalosporium species by
Turner7,8 and reported to have weak antibiotic activity. Ear-
ly structural studies established that 1233A was a β-lactone
with the ring substituents in a trans relationship, but it was
not until 1988 that a Merck group deduced the relative and
absolute configuration at C-7 by chemical degradation and
NMR analysis.9 Three total syntheses10–12 and two partial
syntheses13,14 have since confirmed the structure and stereo-
chemistry; recently the Langlois group completed a new
asymmetric synthesis using asymmetric [2+3] cycloaddi-
tion chemistry.15 Omura has described a number of highly
active simpler analogues.16–20 We now report a concise
asymmetric synthesis of 1233A (1) from three fragments
plus CO2 (Scheme 1) in which all three stereogenic centres
are secured by asymmetric methods.
Scheme 2
Our attempts to create the (E,E)-diene via Heck or Stille
coupling reactions were not very fruitful owing to low
yields, messy reactions, and isomerisation of the diene
Scheme 1

SYNTHESIS
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1656
products.11 Recently, Liebeskind reported a new coupling The key step in our synthesis, the construction of the
of alkenylstannanes and alkenyl iodides which uses the β-lactone ring, required an asymmetric method since the
inexpensive and readily available copper(I) thiophene-2- C-7 stereogenic centre was too remote from the aldehyde
carboxylate as the mediator.27 The union of fragments 2 to offer significant diastereocontrol in C–C bond forming
and 3 using Liebeskind’s procedure provided a fast, effi- reactions. We therefore used an asymmetric [2+2]
cient, and stereoselective route to the desired diene 11 as cycloaddition29 of (trimethylsilyl)ketene (4) to the alde-
shown in Scheme 3. The reaction simply involved addi- hyde 13 mediated by the enantiopure methylaluminoimi-
tion of alkenylstannane 3 to a solution of iodoalkene 2 (2 dazoline 17 to give 4 diastereoisomeric 3-trimethylsilyl
equiv) and copper(I) thiophene-2-carboxylate (1.5 equiv) β-lactones consisting of 2 cis-isomers and 2 trans-isomers
in N-methylpyrrolidinone (NMP). After 5 minutes at (cis/trans 17:1). The two cis-isomers were isolated by col-
room temperature the reaction was complete giving diene umn chromatography in 65% yield during which the
11 in 85% yield as a single stereoisomer. The ease and ligand was recovered. Chiral HPLC analysis revealed a
efficiency of Liebeskind’s procedure makes it a com- d.r. 3:1 relative to the C-7 stereogenic centre in favour of
mendable alternative to traditional Pd(0)-catalysed meth- the desired diastereoisomer (2'R,3'S)-14b. The mixture
ods. The low cost and ready availability of the copper(I) was not separable until the final step.
thiophene-2-carboxylate compensates for the stoichio-
In earlier syntheses of the β-lactone natural products
metric amounts required. With the diene in place, the TBS
lipstatin30 and tetrahydrolipstatin31 we had simply re-
ether in 11 was cleaved with tetrabutylammonium fluo-
placed the trimethylsilyl substituent on the β-lactone cy-
ride (TBAF) and the resultant alcohol 12 oxidised to alde-
cloadducts with a proton, but in the present synthesis we
hyde 13 with the Dess–Martin periodinane (DMP).28
hoped to enlist the trimethylsilyl group in the appendage
of the remaining hydroxymethyl substituent. Unfortunate-
ly, attempts to append the hydroxymethyl group in one
step by trapping the tetrabutylammonium enolate derived
from reaction of 14 and TBAF with gaseous formalde-
hyde was fruitless. However, carboxylation of the tetrabu-
tylammonium enolate was readily accomplished by a
modification of the procedure of Mead32,33 involving slow
•
addition of the β-lactone to a solution of TBAF 3H2O in
THF through which was bubbled dry CO2. After acidic
workup, the crude carboxylic acid was reduced with bo-
rane to give the tert-butyl ester of 1233A 15 in 42% yield.
To complete the synthesis, the tert-butyl ester was cleaved
with trifluoroacetic acid (TFA) in dichloromethane and
the diastereoisomers separated by column chromatogra-
phy. The major isomer was identical by IR and high field
1H and 13C NMR spectroscopy with the data reported by
Wovkulich.11
In conclusion, we have accomplished an asymmetric syn-
thesis of 1233A from cheap starting materials in 4.9%
overall yield for the longest linear sequence of 12 steps.
Noteworthy features include (a) high enantioselectivity in
the asymmetric conjugate reduction leading to the stereo-
genic centre at C-7; (b) efficient and stereoselective con-
struction of the conjugated diene moiety; and (c) asym-
metric [2+2] cycloaddition of a silylketene to an aldehyde
mediated by an enantiopure Lewis acid. A significant stra-
tegic enhancement is the use of the trimethylsilyl group to
both stabilise the ketene and then serve as a handle for the
appendage of the hydroxymethyl group to the oxetanone
ring. The principal detractions are the modest diastereose-
lectivity in the cycloaddition and the disappointing yield
in the borane reduction leading to the α-hydroxymethyl
group in β-lactone 15.
Reactions requiring anhydrous conditions were conducted in flame-
dried apparatus under a static atmosphere of dry argon or N2. Organic
extracts were dried over MgSO4 unless otherwise specified and evap-
orated using a Buchi rotary evaporator. Distillations in which the bath
Scheme 3

SYNTHESIS
November 1998
1657
temperature is recorded were performed with a Kugelrohr apparatus.
Where appropriate, solvents and reagents were dried by standard meth-
ods i.e. by distillation from the usual drying agent prior to use. All re-
actions were magnetically stirred and were monitored by TLC using
Macherey–Nagel Düren Alugram Sil G/UV254 pre-coated aluminium
foil sheets, layer thickness 0.25 mm. Compounds were visualised by
UV (254 nm), then with 20 wt% phosphomolybdic acid in EtOH with
heating. Flash chromatography was performed on Merck silica gel 60
(0.04–0.063 mm, 230–400 mesh) and run under low pressure.
13C NMR (75 MHz, CDCl3): δ = –5.3 (2C, 3), 14.6 (3), 18.5 (0), 18.8
(3), 25.6 (2), 26.1 (3C, 3), 27.3 (2), 32.7 (2), 41.0 (2), 59.5 (2), 63.1
(2), 115.7 (1), 160.2 (0), 167.0 (0).
LRMS (CI mode, NH3): m/z (%) = 315 [(M + H)+, 95], 286 (25), 269
(40), 257 [(M + H – C4H9)+, 100].
Anal. Calcd for C17H34O3Si: C, 64.92; H, 10.90. Found: C, 64.91; H,
10.94.
(+)-Ethyl (R)-8-(tert-Butyldimethylsilyloxy)-3-methyloctanoate (8):
Into a glass tube fitted with a vacuum tight Young’s tap was placed
enoate 6 (9.62 g, 30.6 mmol) in EtOH (12.5 mL) under argon. To the
Optical rotations were recorded on an Optical Activity AA-100 pola-
rimeter at approximately 20°C. IR spectra were recorded on a Perkin–
Elmer 1600 series FTIR spectrometer as thin films supported on NaCl
plates. Absorptions are reported as values in cm–1 and defined as ei-
ther strong (s) or medium (m). Broad absorptions are designated (br).
Weak absorptions are not reported. 1H NMR spectra were recorded in
Fourier Transform mode on a Jeol JNX-GX-270 (270 MHz), Bruker
AC 300 (300 MHz) or Bruker AM 360 (360 MHz) spectrometer in
CDCl3. Chemical shifts are reported in ppm relative to residual
CHCl3 (δ = 7.27). Multiplicities are described using the following ab-
breviations: (s) singlet, (d) doublet, (t) triplet, (q) quartet, (m) multi-
plet, (br) broad. 13C NMR spectra were recorded on a Jeol JNX-GX-
270 (68 MHz), Bruker AC 300 (75 MHz) or Bruker AM 360
(90 MHz) spectrometer in CDCl3 (δ = 77.2). Chemical shifts are re-
ported in ppm relative to the solvent. Multiplicities were determined
using the Distortionless Enhancement by Phase Transfer (DEPT)
spectral editing technique, with secondary pulses at 90˚ and 135˚. C–
H coupling is indicated by an integer 0–3 in parenthesis denoting the
number of coupled protons. MS were run on a VG 70-250-SE or
JEOL MStation JMS-700 spectrometer. Ion mass/charge (m/z) ratios
are reported as values in atomic mass units followed, in parentheses,
by the peak intensity relative to the base peak (100%) and where
shown, the proposed signal assignment. All compounds submitted for
MS analysis were purified by either distillation or column chromatog-
raphy and estimated to be at least 95% pure by NMR and TLC.
•
magnetically stirred solution was added CoCl2 6H2O (319 mg,
1.34 mmol, 4.4 mol%) in EtOH (4 mL) followed by (1S,9S)-1,9-
bis[(tert-butyldimethylsilyloxy)methyl]-5-cyanosemicorrin
(7)22
(746 mg, 1.61 mmol, 5.3 mol%) in EtOH (5.5 mL). On addition of the
semicorrin the mixture changed from a blue to a deep purple colour. To
the mixture was finally added a slightly turbid solution of NaBH4
(2.315 g, 61.2 mmol, 2 equiv) in DMF (19 mL). The now brown mix-
ture was thoroughly degassed via 4 freeze–thaw cycles and then sealed
under vacuum and allowed to warm to r.t. After stirring for 5 d at r.t.,
the internal pressure was eased by careful opening of the Teflon tap and
water (100 mL) was added. The product was extracted with CH2Cl2
(3 × 100 mL). The combined organic extracts were washed with water
(2 × 100 mL), brine (100 mL), dried and concentrated in vacuo to a
brown oil which was chromatographed (silica gel, hexanes/Et2O 95:5)
to give the ester 8 (9.31 g, 96%); [α]D +2.8 (c = 3.42, CHCl3). 1H NMR
spectra (360 MHz) of (+)-8 and (±)-8 recorded in the presence of Eu-
ropium tris[3-heptafluoropropylhydroxymethyl-ene)-(–)-camphorate
[Eu(hfc)3] established an enantiomeric ratio of 20:1.
IR (film): ν = 2931s, 2857s, 1738s, 1255s, 1098s, 837s cm–1.
1H NMR (270 MHz, CDCl3): δ = 0.03 (6H, s, SiMe2), 0.88 (9H, s, t-
Bu), 0.91 (3H, d, J = 6.3 Hz, C3Me), 1.24 (3H, t, J = 7.1 Hz,
CH3CH2O), 1.29 (6H, br m), 1.48 (2H, m), 1.90 (1H, br m, C3H), 2.07
(1H, dd, J = 14.5, 7.9 Hz, C2HAHB), 2.27 (1H, dd, J = 14.3, 6.0 Hz,
C2HAHB), 3.58 (2H, t, J = 6.9 Hz, CH2OSi), 4.11 (2H, q, J = 7.1 Hz,
CH3CH2O).
Ethyl (E)-8-(tert-Butyldimethylsilyloxy)-3-methyloct-2-enoate (6):
To a solution of 1-(tert-butyldimethylsilyloxy)-5-iodopentane34,35
(377 mg, 1.15 mmol) in Et2O (5 mL) and pentane (3 mL) at –75°C
was added 1.7 M t-BuLi in hexanes (1.4 mL, 2.38 mmol, 2 equiv).
The pale yellow solution was warmed to 0°C and THF (200 µL,
2.46 mmol) was added. The mixture of 1-(tert-butyldimethylsilyloxy)-
5-lithiopentane was stirred for 10 min then cooled to –20°C and added
via cannula to another reaction flask containing a solution of trimethyl-
silylmethylcopper at –80°C prepared as follows: to a suspension of CuI
(220 mg, 1.16 mmol) in Et2O (10 mL) at –75°C was added 1.0 M trim-
ethylsilylmethyllithium in pentane (1.15 mL, 1.15 mmol). The pale yel-
low mixture was warmed to 0°C and stirred for 10 min.
13C NMR (68 MHz, CDCl3): δ = –5.1 (2C, 3), 14.4 (3), 18.5 (0), 19.9
(3), 26.1 (4C, 3 and 2), 26.9 (2), 30.5 (1), 33.0 (2), 36.9 (2), 42.1 (2),
60.2 (2), 63.3 (2), 173.4 (0).
LRMS (CI mode, NH3): m/z (%) = 317 [(M + NH4)+, 100], 259 (20),
57 (28).
Anal. Calcd for C17H36O3Si: C, 64.51; H, 11.46. Found: C, 64.44; H,
11.57.
(+)-(R)-8-(tert-Butyldimethylsilyloxy)-3-methyloctanal (9):
1.5 M DIBALH in toluene (10.1 mL, 15.15 mmol) was added drop-
wise to a solution of ester 8 (4.7 g, 14.85 mmol) in toluene (60 mL) at
–80°C. The reaction was stirred for 30 min and then quenched by
addition of MeOH (40 mL). The mixture was warmed to 0°C then
poured into a solution of sodium potassium tartrate (75 g) in water
(300 mL). The mixture was stirred vigorously for 30 min and then
poured into Et2O (300 mL) and brine (100 mL). The aqueous phase
was extracted with Et2O (100 mL) and combined organic layers were
washed with brine (100 mL), dried and concentrated in vacuo and the
residue purified by column chromatography (silica gel, hexanes/Et2O
95:5) to give aldehyde 9 (3.81 g, 94%) as a colourless oil after Kugel-
rohr distillation; bp 85°C (bath)/0.8 Torr; [α]D +9.0 (c = 3.535,
CHCl3).
After addition of the alkyllithium to the cuprate, the resulting mixed
cuprate was warmed to 0°C and stirred for 10 min During this time
the mixture became orange and finally pale tan. The solution was then
cooled to –90°C and ethyl but-2-ynoate (112 mg, 1.0 mmol) was add-
ed as a solution in Et2O (1.5 mL). The internal temperature was main-
tained at or slightly below –90°C during the addition. The reaction
was stirred for 5 min and then quenched (at –90°C) with sat. aq
NH4Cl (5 mL) and warmed to r.t. over 1 h. The mixture was poured
into Et2O (100 mL) and water (50 mL). The organic phase was
washed with water (2 × 25 mL) and brine (25 mL) then dried, filtered
and concentrated in vacuo to a colourless oil which was chromato-
graphed (silica gel, hexanes/Et2O 97:3) to give (E)-6 (214 mg, 68%)
as a colourless oil; bp 110°C (bath/0.5 Torr).
IR (film): ν = 2933s, 2858s, 1718s, 1649s, 1472s, 1386m, 1367s,
IR (film): ν = 2930s, 2857s, 1728s, 1463s, 1387s, 1361m, 1255s,
1256s, 1222s, 1147s, 1100s, 1044m, 836s cm–1.
1099s, 835s cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.03 (6H, s, SiMe2), 0.88 (9H, s, t-
Bu), 1.26 (3H, t, J = 7.2 Hz, CH3CH2O), 1.32–1.50 (6H, m), 2.13 (2H,
t, J = 8.8 Hz), 2.14 (3H, d, J = 1.1 Hz, C3Me), 3.59 (2H, t, J = 6.5 Hz,
CH2OSi), 4.13 (2H, q, J = 7.2 Hz, CH3CH2O), 5.64 (1H, sextet, J =
1.1 Hz, C2H).
1H NMR (270 MHz, CDCl3): δ = 0.02 (6H, s, SiMe2), 0.87 (9H, s, t-
Bu), 0.93 (3H, d, J = 6.7 Hz, C3Me), 1.29 (6H, m), 1.50 (2H, m), 2.03
(1H, m, C3H), 2.19 (1H, ddd, J = 15.8, 7.5, 2.3 Hz, C2HAHB), 2.37
(1H, ddd, J = 15.8, 5.6, 2.1 Hz, C2HAHB), 3.57 (2H, t, J = 6.3 Hz,
CH2OSi), 9.73 (1H, t, J = 2.3 Hz, CHO).

SYNTHESIS
Papers
1658
13C NMR (50 MHz, CDCl3): δ = –5.3 (2C, 3), 18.4 (0), 20.0 (3), 25.95
(2), 26.00 (3C, 3), 26.8 (2), 28.1 (1), 32.8 (2), 36.9 (2), 51.1 (2), 63.1
(2), 202.8 (0).
alkenylstannane 3 (632 mg, 1.47 mmol) in NMP (3 mL). The mixture
was stirred for 5 min then diluted with Et2O (50 mL) and filtered
through a bed of Celite. The resulting clear ethereal solution was
washed with water (3 × 25 mL), brine (25 mL), dried, filtered and
concentrated to a pale yellow oil which was chromatographed (silica
gel, hexanes/Et2O 99:1 to 96:4) to yield recovered iodoalkene 2
(652 mg, 93% recovery) and the diene 11 (535 mg, 85%) as a colour-
less oil: [α]D –11.2 (c = 3.12, CHCl3).
LRMS (CI mode, NH3): m/z (%) = 289 [(M + NH4)+, 100].
Anal. Calcd for C15H32O2Si: C, 66.12; H, 11.84. Found: C, 66.19; H,
11.79.
(+)-(R)-O-(tert-Butyldimethylsilyl)-6-methylnon-8-yn-1-ol (10):
A solution of aldehyde 9 (291 mg, 1.07 mmol) and 1-diazo-1-
(dimethoxyphosphoryl)propan-2-one25 (307 mg, 1.6 mmol,
1.5 equiv) in anhyd MeOH was cooled to 0°C and anhyd K2CO3
(310 mg, 2.24 mmol, 2.1 equiv) added. The yellow mixture was
warmed to r.t. and stirred for 14 h. The reaction was quenched by
addition of sat. aq NH4Cl (5 mL) and extracted with hexanes (20 mL).
The organic layer was dried (MgSO4), filtered and concentrated in
vacuo to a yellow oil which was chromatographed (silica gel, hex-
anes/Et2O 95:5) to give alkyne 10 (236 mg, 82%) as a colourless oil;
bp 50°C (bath)/0.5 Torr; [α]D +0.8 (c = 2.9, CHCl3).
IR (film): ν = 3314m, 2955s, 2923s, 2857s, 1472m, 1255s, 1099s,
836s, 775s cm–1.
IR (film): ν = 2929s, 2856s, 1710s, 1625m, 1472m, 1462m, 1380m,
1366s, 1250s, 1141s, 1099s, 836s, 775s cm–1.
1H NMR (270 MHz, CDCl3): δ = 0.05 (6H, s, SiMe2), 0.82 (3H, d, J
= 6.5 Hz, C7Me), 0.89 (9H, s, t-Bu), 1.05–1.75 (9H, m), 1.48 (9H, s,
O-t-Bu),1.80 (1H, dd, J = 13.0, 7.8 Hz, C6HAHB), 1.98 (3H, d, J =
1.0 Hz, C5Me), 2.07 (1H, dd, J = 12.8, 5.6 Hz, C6HAHB), 2.19 (3H,
d, J = 1.0 Hz, C3Me), 3.60 (2H, t, J = 6.3 Hz, CH2OSi), 5.58 (1H, br
s, C4H), 5.66 (1H, br s, C2H).
13C NMR (68 MHz, CDCl3): δ = –5.1 (2C, 3), 18.3 (3), 19.4 (2C, 3),
19.4 (0), 26.0 (3C, 3), 26.1 (2), 26.8 (2), 28.3 (3C, 3), 30.9 (1), 32.9
(2), 36.9 (2), 49.0 (2), 63.2 (2), 79.4 (0), 119.3 (1), 129.5 (1), 140.5
(0), 152.7 (0), 166.7 (0).
LRMS (CI mode, NH3): m/z (%) = 442 [(M + NH4)+, 50%], 425 [(M
+ H)+, 100], 386 [(M + NH4 – C4H8)+, 5], 369 [(M + H – C4H8)+, 10),
311 [(M + H – C8H18)+, 30).
1H NMR (270 MHz, CDCl3): δ = 0.05 (6H, s, SiMe2), 0.89 (9H, s, t-
Bu), 0.98 (3H, d, J = 6.9 Hz, C6Me), 1.15–1.75 (9H, m), 1.93 (1H, t,
J = 2.5 Hz, C9H), 2.05 (1H, ddd, J = 16.7, 6.6, 2.5 Hz, C7HAHB), 2.16
(1H, ddd, J = 16.7, 5.7, 2.5 Hz, C7HAHB), 3.60 (2H, t, J = 6.4 Hz,
CH2OSi).
HRMS (CI mode, NH3): found, (M + NH4)+, 442.3743. C25H48O3Si
+ NH4 requires 442.3716.
13C NMR (68 MHz, CDCl3): δ = –5.1 (2C, 3), 18.5 (0), 19.6 (3), 25.9
(2C, 2), 26.2 (3C, 3), 27.0 (2), 32.5 (1), 33.0 (2), 36.1 (2), 63.4 (2),
69.2 (0), 83.5 (1).
(–)-tert-Butyl (R)-(E,E)-12-Hydroxy-3,5,7-trimethyldodeca-2,4-
dienoate (12):
To a solution of the silyl ether 11 (210 mg, 0.494 mmol) in THF
LRMS (CI mode, NH3): m/z (%) = 286 [(M + NH4)+, 15], 269 [(M +
H)+, 100].
(7 mL) at 0°C was added a solution of TBAF 3H2O (314 mg,
•
Anal. Calcd for C16H32OSi: C, 71.57; H, 12.01. Found: C, 71.69; H,
12.09.
1.2 mmol, 2.4 equiv) in THF (3 mL). The yellow solution was
warmed to r.t., stirred for 1 h then quenched with water (1 mL). The
organic phase was diluted with Et2O (5 mL) and the aqueous phase
was extracted with Et2O (5 mL). Combined ethereal extracts were
washed with brine (5 mL), dried, filtered and concentrated to a co-
lourless oil which was chromatographed (silica gel, hexanes/Et2O
80:20 to 60:40) to yield the alcohol 12 (138 mg, 90%) as a colourless
oil; [α]D –12.6 (c = 3.15, CHCl3).
(–)-(R)-(E)-O-(tert-Butyldimethylsilyl)-9-iodo-6,8-dimethylnon-
8-en-1-ol (2):
To a suspension of ZrCl2 (1.09 g, 3.72 mmol, 1 equiv) in 1,2-dichlo-
roethane (10 mL) was added 2.0 M Me3Al in toluene (5.6 mL,
11.2 mmol, 3 equiv). The lemon yellow solution was stirred at r.t. for
15 min then the acetylene 10 (1.00 g, 3.72 mmol) in 1,2-dichloro-
ethane (10 mL) was added. After stirring for 12 h the reaction had
become a darker yellow colour. The reaction was cooled to –20°C
and iodine (1.51 g, 5.95 mmol, 1.6 equiv) added as a solution in THF
(8 mL). The reaction was carefully quenched with THF/H2O (1:1,
20 mL) at –10°C and warmed slowly to r.t. over 30 min. The mixture
was poured into Et2O (100 mL) and water (50 mL). The aqueous
phase was extracted with Et2O (20 mL) and the combined organic
layers were washed with brine (50 mL), dried and concentrated in
vacuo to a colourless turbid oil which was chromatographed (silica
gel, hexanes/Et2O 98:2) to give iodoalkene 2 (1.35 g, 88%) as a co-
lourless oil; [α]D –1.1 (c = 3.185, CHCl3).
IR (film): ν = 3365br s, 2929s, 2858s, 1708s, 1622s, 1456s, 1391s,
1367s, 1291m, 1240s, 1141s, 1043m, 888m cm–1.
1H NMR (270 MHz, CDCl3): δ = 0.80 (3H, d, J = 6.5 Hz, C7Me),
1.1–1.7 (9H, m), 1.46 (9H, s, t-Bu), 1.76 (3H, d, J = 1.2 Hz, C5Me),
1.79 (1H, dd, J = 12.7, 8.1 Hz, C6HAHB), 1.93 (1H, br s, OH), 2.05
(1H, dd, J = 12.7, 5.8 Hz, C6HAHB), 2.17 (3H, d, J = 1.2 Hz, C3Me),
3.61 (2H, t, J = 6.6 Hz, CH2OH), 5.55 (1H, m, C4H), 5.65 (1H, s br,
C2H).
13C NMR (68 MHz, CDCl3): δ = 18.3 (3), 19.3 (2C, 3), 19.3 (0), 26.0
(2), 26.8 (2), 28.2 (3C, 3), 30.9 (1), 32.7 (2), 36.8 (2), 48.9 (2), 62.8
(2), 79.5 (0), 119.3 (1), 129.5 (1), 140.5 (0), 152.7 (0), 166.7 (0).
LRMS (CI mode, NH3): m/z (%) = 328 [(M + NH4)+, 100], 311 [(M
+ H)+, 90], 272 [(M + NH4 – C4H8)+, 70], 255 [(M + H – C4H8)+, 15).
HRMS (CI mode, NH3): found, (M + NH4)+, 328.2842. C19H34O3 +
NH4 requires 328.2851.
IR (film): ν = 2928s, 2856s, 1462m, 1255s, 1099s, 836s, 775s cm–1.
1H NMR (270 MHz, CDCl3): δ = 0.04 (6H, s, SiMe2), 0.81 (3H, d, J
= 6.6 Hz, C6Me), 0.90 (9H, s, t-Bu), 1.0–1.7 (9H, m), 1.79 (3H, br s,
C8Me), 1.98 (1H, dd, J = 13.5, 8.4 Hz, C7HAHB), 2.19 (1H, dd, J =
13.5, 5.9 Hz, C7HAHB), 3.60 (2H, t, J = 6.3 Hz, CH2OSi), 5.82 (1H,
s br, C9H).
(–)-tert-Butyl (R)-(E,E)-3,5,7-Trimethyl-12-oxododeca-2,4-di-
enoate (13):
13C NMR (68 MHz, CDCl3): δ = –5.1 (2C, 3), 18.5 (0), 19.5 (3), 23.9
(3), 26.2 (3C, 3), 26.2 (2), 27.0 (2), 31.1 (1), 33.0 (2), 36.9 (2), 47.8
(2), 63.4 (2), 75.4 (1), 147.3 (0).
To a solution of the alcohol 12 (385 mg, 1.24 mmol) in CH2Cl2
(12 mL) was added the Dess–Martin periodinane28,36 (873 mg,
2.06 mmol, 1.7 equiv). The mixture was stirred for 2 h then quenched
with sat. aq Na2S2O3/sat. aq NH4Cl (1:1, 50 mL). The mixture was
stirred vigorously for 10 min then the organic phase was diluted with
CH2Cl2 (20 mL) and water (20 mL). The aqueous phase was extracted
with CH2Cl2 (25 mL) and the combined extracts were washed with
sat. NaHCO3 (5 mL), dried, filtered and concentrated to a colourless
oil which was chromatographed (silica gel, hexanes/Et2O 90:10) to
yield the aldehyde 13 (332 mg, 87%) as a colourless oil; [α]D–13.7 (c
= 3.41, CHCl3).
HRMS (CI mode, NH3): found, (M + NH4)+, 428.1823. C17H35IOSi +
NH4 requires 428.1847.
(–)-tert-Butyl (R)-(E,E)-12-(tert-Butyldimethylsilyloxy)-3,5,7-tri-
methyldodeca-2,4-dienoate (11):
To a solution of the iodoalkene 2 (1.21 g, 2.95 mmol, 2 equiv) in NMP
(5 mL) was added copper(I) thiophene-2-carboxylate27 (422 mg,
2.21 mmol, 1.5 equiv). To this suspension was added a solution of the

SYNTHESIS
November 1998
1659
IR (film): ν = 2931s, 2716m, 1728s, 1708s, 1622m, 1456m, 1391m,
(10 mL), dried and concentrated in vacuo. The crude acid was split
into 2 batches (ca. 55 mg each) for borane experiments. The following
procedure is representative: to the crude acid (ca. 55 mg) in THF (5
1367m, 1239m, 1140s cm –1
.
1H NMR (270 MHz, CDCl3): δ = 0.81 (3H, d, J = 6.4 Hz, C7Me),
1.1–1.6 (7H, m), 1.48 (9H, s, t-Bu), 1.78 (3H, d, J = 1.1 Hz, C5Me),
1.81 (1H, dd, J = 12.8, 8.4 Hz, C6HAHB), 2.06 (1H, dd, J = 12.8, 5.6
Hz, C6HAHB), 2.19 (3H, d, J = 1.1 Hz, C3Me), 2.43 (2H, dt, J = 6.2,
1.5 Hz, C11H2), 5.56 (1H, m, C4H), 5.66 (1H, br s, C2H), 9.77 (1H,
t, J = 1.6 Hz, CHO).
•
mL) at 0°C was added 1.0 M BH3 THF in THF (0.6 mL, 0.6 mmol,
1.6 equiv). The reaction was warmed to r.t. and stirred for 1 h. The
reaction was then quenched with MeOH (5 mL) and stirred for 10 min
The volatiles were removed in vacuo and the resulting oil was chro-
matographed (silica gel, hexanes/Et2O 60:40 to 40:60) to yield the
alcohol 15 (21 mg, 42%, over 2 steps) as a colourless oil; [α]D +9.2
(c = 1.515, CHCl3).
13C NMR (68 MHz, CDCl3): δ = 18.5 (3), 19.5 (3), 19.6 (3), 22.5 (2),
26.8 (2), 28.5 (3C, 3), 31.0 (1), 36.7 (2), 44.1 (2), 49.1 (2), 79.7 (2),
119.5 (1), 129.8 (1), 140.5 (0), 152.8 (0), 166.9 (0), 202.9 (1).
LRMS (CI mode, NH3): m/z (%) = 326 [(M + NH4)+, 100], 309 [(M
+ H)+, 20], 270 [(M + NH4 – C4H8)+, 70], 253 [(M + H – C4H8)+, 5).
HRMS (CI mode, NH3): found, (M + NH4)+, 326.2692. C19H32O3 +
NH4 requires 326.2692.
IR (film): ν = 3497s br, 2929s, 1824s, 1705s, 1623s, 1456s, 1367s,
1330m, 1240s, 1141s, 1043m, 885m, 834m cm–1.
1H NMR (270 MHz, CDCl3): δ = 0.83 (3H, d, J = 6.4 Hz, C7Me), 1.0–
2.0 (9H, m + OH), 1.47 (9H, s, t-Bu), 1.78 (3H, d, J = 1.1 Hz, C5Me),
1.83 (1H, dd, J = 12.8, 8.0 Hz, C6HAHB), 2.06 (1H, dd, J = 12.8, 6.2
Hz, C6HAHB), 2.19 (3H, d, J = 1.1 Hz, C3Me), 3.39 (1H, q, J = 4.6
Hz, C3’H), 3.88 (1H, dd, J = 11.5, 4.1 Hz, CHAHBOH), 4.03 (1H, dd,
J = 11.7, 4.8 Hz, CHAHBOH), 4.58 (1H, ddd, J = 7.1, 5.7, 4.1 Hz,
C2’H), 5.57 (1H, br s, C4H), 5.67 (1H, br s, C2H).
[2+2] Cycloaddition to â-Lactones 14a,b:
To a solution of the bis-sulfonamide 16 (342 mg, 0.517 mmol) in
toluene (20 mL) was added 2.0 M Me3Al in toluene (0.25 mL,
0.50 mmol). The chiral Lewis acid was stirred at r.t. for 10 min then
cooled to –70°C whereupon the aldehyde 13 (304 mg, 0.985 mmol)
in toluene (5 mL + 2 × 1 mL rinses) was added dropwise. The mix-
ture was stirred for 5 min then (trimethylsilyl)ketene (4)37 (146 mg,
1.28 mmol) in toluene (5 mL) was added dropwise. The reaction
was stirred warming to 0°C over 2 h when it was quenched with sat.
aq NH4Cl (5 mL). The organic phase was diluted with Et2O (20 mL)
and the aqueous phase was extracted with more Et2O (20 mL). The
combined extracts were washed with 1 N HCl (10 mL), brine
(20 mL), dried, filtered and concentrated to a colourless oil which
was chromatographed (silica gel, hexanes/Et2O 95:5 to 80:20) to
yield a mixture of the cis β-lactones 14a and 14b (279 mg, 67%) as
a colourless oil (3:1 ratio in favour of 14b) and another fraction con-
taining a 1:1.3 cis/trans mixture (32 mg, 8%) also as a colourless oil.
The NMR spectra for the mixture 14a,b indicated a single com-
pound; therefore the d.r. was determined by recording the spectra in
the presence of (–)-(R)-1-(9-anthryl)-2,2,2-trifluoroethanol38 in
which case the doublets (J = 6.1 Hz) arising from the C3' methine
signals were clearly distinguishable (14a δ = 3.314 and 14b δ =
3.300). The total yield of β-lactone = 75%; cis/trans 94:6; [α]D +17.1
(c = 2.765, CHCl3).
13C NMR (50 MHz, CDCl3): δ = 18.6 (3), 19.7 (3), 19.7 (3), 25.4 (2),
26.8 (2), 28.5 (3C, 3), 31.0 (1), 34.2 (2), 36.7 (2), 49.1 (1), 58.3 (2),
58.8 (1), 75.1 (1), 79.9 (0), 119.5 (1), 129.8 (1), 140.6 (0), 152.9 (0),
167.0 (0), 169.9 (0).
LRMS (EI mode): m/z (%) = 324 [(M – C4H8)+•, 16], 308 (15), 280
(5), 162 (10), 125 (100), 122 (24), 95 (17), 57 (28).
HRMS (EI mode): found, (M – C4H8)+•, 324.1933. C18H28O5 requires
324.1937.
(7R)-(E,E)-11-[(2R,3R)-3-Hydroxymethyl-4-oxooxetan-2-yl]-
3,5,7-trimethylundeca-2,4-dienoic Acid (1233A) (1):
To a solution of the ester 15 (33 mg, 0.087 mmol) in CH2Cl2 (2 mL)
at r.t. was added TFA (1.5 mL). The mixture was stirred at r.t. for
20 min whereupon the volatiles were removed in vacuo. CH2Cl2
(2 mL) was added and evaporated. This was repeated twice and the
crude product purified by chromatography (silica gel, CH2Cl2/MeOH
99:1 to 92:8) to give the natural product 1233A (1) (15 mg, 53%) as
a colourless oil; [α]D +28.8 (c = 0.25, CHCl3) (Lit.10 +28.6 (c = 0.62,
CHCl3).
UV (EtOH): λmax (ε) = 271 nm (12,030) [Lit.8 267 nm (12,150)].
IR (film): ν = 3500–2500br s, 3389br s, 2925s, 2855s, 1820s, 1689s,
1614s, 1462m, 1379m, 1256m, 1142m cm–1.
IR (film): ν = 2929s, 2862s, 1805s, 1705s, 1623s, 1456s, 1390s,
1367s, 1332m, 1292s, 1253s, 1141s, 1004m, 913m, 847s cm–1.
1H NMR (270 MHz, CDCl3): δ = 0.20 (9H, s, Me3Si), 0.80 (3H, d, J
= 6.5 Hz, C7Me), 1.0–1.6 (9H, m), 1.45 (9H, s, t-Bu), 1.75 (3H, d, J
= 1.2 Hz, C5Me), 1.80 (1H, dd, J = 12.8, 7.8 Hz, C6HAHB), 2.03 (1H,
dd, J = 12.8, 6.6 Hz, C6HAHB), 2.16 (3H, d, J = 1.2 Hz, C3Me), 3.31
(1H, d, J = 6.1 Hz, C3’H), 4.54 (1H, ddd, J = 9.2, 6.1, 4.8 Hz, C2’H),
5.54 (1H, m, C4H), 5.63 (1H, br s, C2H).
1H NMR (360 MHz, CDCl3): δ = 0.85 (3H, d, J = 6.1 Hz, H3''), 1.10–
1.57 (6H, m), 1.58–1.99 (5H, m), 1.82 (3H, d, J = 1.1 Hz, H1''), 2.09
(1H, dd, J = 12.8, 6.4 Hz, H6), 2.25 (3H, d, J = 1.1 Hz, H2''), 3.42 (1H,
q, J = 4.3 Hz, H3'), 3.90 (1H, dd, J = 11.4, 4.0 Hz, H5'), 4.06 (1H, dd,
J = 11.6, 4.6 Hz, H5'), 4.60 (1H, ddd, J = 7.3, 5.8, 4.1 Hz, H2'), 5.69
(1H, s, H2), 5.73 (1H, s, H4).
13C NMR (68 MHz, CDCl3): δ = –1.0 (3C, 3), 18.4 (3), 19.4 (3), 19.5
(3), 26.7 (2C, 2), 28.4 (3C, 3), 30.9 (1), 33.6 (2), 36.7 (2), 46.4 (1),
49.0 (2), 74.1 (1), 79.6 (0), 119.4 (1), 129.7 (1), 140.4 (0), 152.7 (0),
166.8 (0), 171.0 (0).
13C NMR (90 MHz, CDCl3): δ = 18.7 (3), 19.6 (3), 20.2 (3), 25.4 (2),
26.8 (2), 31.1 (1), 34.2 (2), 36.8 (2), 49.2 (2), 58.3 (2), 58.8 (1), 75.1
(1), 116.6 (1), 129.7 (1), 142.3 (0), 157.2 (0), 169.9 (0), 171.0 (0).
HRMS (EI mode): found, M+•, 324.1928. C18H28O5 requires
324.1937 (error –2.7 ppm).
LRMS (CI mode, NH3): m/z (%) = 423 [(M + H)+, 100], 367 (18), 349
(30).
Anal. Calcd for C24H42O4Si: C, 68.20; H, 10.02. Found: C, 68.43; H,
9.97.
tert-Butyl (E)-3-(Tributylstannyl)but-2-enoate (3):
To a solution of but-2-ynoic acid (1.268 g, 15.08 mol) in CH2Cl2
(15 mL) at r.t. was added a solution of tert-butyl trichloroacetimidate39
(6.25 g, 28.60 mmol, 1.9 equiv). The reaction was stirred for 10 min
whereupon the crystals of trichloroacetamide were filtered and
washed with Et2O/hexanes (1:1, 20 mL). The filtrate was concentrat-
ed to a yellow oil by distillation, at atmospheric pressure, then chro-
matographed (silica gel, hexanes/Et2O 95:5). The solvent was re-
moved by distillation to give the ester 3 (1.58 g, 75%) as a colourless
oil; bp 100°C (bath)/20 Torr.
(+)-tert-Butyl (7R)-(E,E)-11-[(2R,3R)-3-Hydroxymethyl-4-oxo-
oxetan-2-yl]-3,5,7-trimethylundeca-2,4-dienoate (15):
•
Through a solution of TBAF 3 H2O (105 mg, 0.402 mmol, 1.1 equiv)
in THF (10 mL) was bubbled CO2 via a syringe needle for 10 min.
The mixture was cooled to –78°C and CO2 bubbling was continued.
To this mixture was added the silyl β-lactones 14a,b (110 mg,
0.26 mmol) in THF (1.0 mL + 0.5 mL rinse) via a syringe pump over
1 h. CO2 bubbling was stopped and the reaction warmed to r.t. then
poured into 1 N HCl (10 mL). The product was extracted with CH2Cl2
(3 × 10 mL) and the combined organic layers were washed with brine
1H NMR (200 MHz, CDCl3): δ = 1.43 (9H, s), 1.91 (3H, s).
13C NMR (90 MHz, CDCl3): δ = 3.7 (3), 28.0 (3C, 3), 73.8 (0), 82.86
(0), 82.92 (0), 152.8 (0).

SYNTHESIS
Papers
1660
Stannylcupration of the ester 3 was accomplished by the procedure of
Piers.40 To a suspension of CuCN (1.11 g, 12.4 mmol, 1.2 equiv) in
THF (30 mL) at –70°C was added 2.5 M BuLi in hexanes (10.0 mL,
25.0 mmol, 2.5 equiv). The mixture was warmed to –30 ˚C and stirred
until homogeneous (10 min). The yellow mixture was cooled back to
–70 ˚C and Bu3SnH (6.6 mL, 7.25 g, 24.9 mol, 2.5 equiv) added neat.
Slight foaming of the solution occurred. The stannylcuprate was
stirred for 5 min at –75 ˚C whereupon t-BuOH (920 mg, 12.42 mmol,
1.2 equiv) added as a solution in THF (6 mL). More vigorous foaming
occurred. To the now red mixture was added the tert-butyl but-2-
ynoate (1.45 g, 10.34 mmol) in THF (9 mL). The reaction was main-
tained below –75°C for 30 min then quenched with a pH 8 solution of
NH3/sat. NH4Cl (25 mL), warmed to r.t. and poured into Et2O/water.
The emulsion was filtered through Celite and the aqueous phase ex-
tracted with Et2O (2 × 100 mL). The combined ethereal layers were
washed with brine (50 mL), dried and concentrated to a colourless oil
which was chromatographed (silica gel, hexanes/Et2O 99:1 to 96:4)
to yield the product 3 (4.06 g, 91%) as a colourless oil. An analytical
sample may be prepared by Kugelrohr distillation [bp 100 °C (bath)/
0.5 Torr].
(1) Brown, M. S.; Goldstein, J. L. Angew. Chem., Int. Ed. Engl.
1986, 25, 583.
(2) Goldstein, J. L.; Brown, M. S. Nature 1990, 343, 425.
(3) Omura, S.; Tomoda, H.; Kumagai, H.; Greenspan, M. D.; Yud-
kovitz, J. B.; Chen, J. S.; Alberts, A. W.; Martin, I.; Mochales,
S.; Monaghan, R. L.; Chabala, J. C.; Schwartz, R. E.; Patchett,
A. A. J. Antibiot. 1987, 40, 1356.
(4) Greenspan, M. D.; Yudkovitz, J. B.; Lo, C. L.; Chen, J. S.;
Alberts, A. W.; Hunt, V. M.; Chang, M. N.; Yang, S. S.;
Thompson, K. L.; Chiang, Y. P.; Chabala, J. C.; Monaghan,
R. L.; Schwartz, R. E. Proc. Natl. Acad. Sci. U.S.A. 1987, 84,
7488.
(5) Tomoda, H.; Kumagai, H.; Tanaka, Y.; Omura, S. J. Antibiot.
1992, 46, 1139.
(6) Greenspan, M. D.; Bull, H. G.; Yudkovitz, J. B.; Hanf, D. P.;
Alberts, A. W. J. Biochem. 1993, 289, 889.
(7) Aldridge, D. C.; Giles, D.; Turner, W. B. J. Chem. Soc., Chem.
Commun. 1970, 639.
(8) Aldridge, D. C.; Giles, D.; Turner, W. B. J. Chem. Soc. C 1971,
3888.
IR (film): ν = 2958s, 2927s, 2872s, 2853s, 1711s, 1598m, 1457m,
(9) Chiang, Y. C. P.; Chang, M. N.; Yang, S. S.; Chabala, J. C.;
Heck, J. V. J. Org. Chem. 1988, 53, 4599.
(10) Chiang, Y. C. P.; Yang, S. S.; Heck, J. V.; Chabala, J. C.;
Chang, M. N. J. Org. Chem. 1989, 54, 5708.
(11) Wovkulich, P. M.; Shankaran, K.; Kiegiel, J.; Uskokovic, M. R.
J. Org. Chem. 1993, 58, 832.
(12) Mori, K.; Takahashi, Y. Liebigs Ann. Chem. 1991, 1057.
(13) Wattanasin, S.; Do, H. D.; Bhongle, N.; Kathawala, F. G.
J. Org. Chem. 1993, 58, 1610.
1366s, 1341m, 1148s, 865m cm–1.
1H NMR (360 MHz, CDCl3): δ = 0.92 (15H, m), 1.32 (6H, m), 1.47
(6H, m, 1.49 (9H, s), 2.36 (3H, d, J = 1.8 Hz), 5.86 (1H, q, J = 1.8 Hz).
13C NMR (90 MHz, CDCl3): δ = 9.6 (3C, 2), 13.8 (3C, 3), 22.3 (3),
27.5 (3C, 2), 28.5 (3C, 3), 29.2 (3C, 2), 79.9 (0), 130.2 (1), 164.4 (0),
166.7 (0).
LRMS (EI mode): m/z (%) = 431 (M+, 10), 375 (100), 319 (100), 263
(30), 233 (10), 205 (30), 177 (30), 135 (12), 121 (15), 57 (60), 41 (32).
Anal. Calcd for C20H40O2Sn: C, 55.71; H, 9.35. Found: C, 55.73; H,
9.32.
(14) Guanti, G.; Banfi, L.; Schmid, G. Tetrahedron Lett. 1994, 35,
4239.
(15) Dirat, O.; Kouklovsky, C.; Langlois, Y. private communication.
(16) Hashizume, H.; Ito, H.; Kanaya, N.; Nagashima, H.; Usui, H.;
Oshima, R.; Kanao, M.; Tomoda, H.; Sunazuka, T.; Nagamistu,
T.; Kumagai, H.; Omura, S. Heterocycles 1994, 38, 1551.
(17) Hashizume, H.; Ito, H.; Yamada, K.; Nagashima, H.; Kanao,
M.; Tomoda, H.; Sunazuka, T.; Kumagai, H.; Omura, S. Chem.
Pharm. Bull. 1994, 42, 512.
(18) Hashizume, H.; Ito, H.; Kanaya, N.; Yamada, K.; Nagashima,
H.; Usui, H.; Oshima, R.; Kanao, M.; Tomoda, H.; Sunazuka,
T.; Kumagai, H.; Omura, S. Chem. Pharm. Bull. 1994, 42, 1272.
(19) Hashizume, H.; Ito, H.; Morikawa, T.; Kanaya, N.; Nagashima,
H.; Usui, H.; Tomoda, H.; Sunazuka, T.; Kumagai, H.; Omura,
S. Chem. Pharm. Bull. 1994, 42, 2097.
(–)-(S,S)-N,N'-Bis(4-tert-butyl-2,6-dimethylphenylsulfonyl)-1,2-
diphenylethylenediamine (17):
To a solution of the diamine 1641 (264 mg, 1.24 mmol) in CH2Cl2
(6 mL) at r.t. was added Et3N (0.57 mL, 4.09 mmol) and DMAP (24
mg, 0.2 mmol). The colourless solution was stirred at r.t. and a solu-
tion of 4-tert-butyl-2,6-dimethylbenzenesulfonyl chloride42 (648 mg,
2.48 mmol) in CH2Cl2 (2 mL + 2 × 1 mL rinse) was added dropwise
via syringe. The reaction stirred at r.t. for 1 h then poured into
CH2Cl2/1 N HCl (1:1, 50 mL). The aqueous layer was extracted with
CH2Cl2 (20 mL) and the combined organic layers were washed with
brine (20 mL), dried, filtered and concentrated in vacuo to a solid
foam which was chromatographed (silica gel, hexanes/Et2O 90:10 to
60:40) to give 17 as a white solid foam (738 mg, 90%); [α]D –89.0 (c
= 0.52, CHCl3)
(20) Tomoda, H.; Kumagai, H.; Ogawa, Y.; Sunazuka, T.; Hashizu-
me, H.; Nagashima, H.; Omura, S. J. Org. Chem. 1997, 62,
2161.
IR (CH2Cl2): ν = 3374s, 3053s, 2968s, 1596m, 1421m, 1321m,
(21) Bertz, S. H.; Eriksson, M.; Miao, G.; Snyder, J. P. J. Am. Chem.
Soc. 1996, 118, 10906.
(22) Pfaltz, A. In Modern Synthetic Methods; Scheffold, R., Ed.;
Springer: Berlin, 1989; Vol. 5; pp 199.
(23) Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Perkin Trans. 1
1977, 869.
(24) Ohira, S. Synth. Commun. 1989, 19, 561.
(25) Callant, P.; D'Haenens, L.; Vandewalle, M. Synth. Commun.
1984, 14, 155.
1265s, 1174m, 1146m cm–1.
1H NMR (270 MHz, CDCl3): δ = 1.23 (18H, s), 2.50 (12H, s), 4.41
(2H, dd, J = 3.6, 2.0 Hz), 6.00 (2H, dd, J = 3.6, 2.2 Hz, NH), 6.61 (4H,
d, J = 6.8 Hz), 6.86 (10H, m).
13C NMR (68 MHz, CDCl3): δ = 23.3 (4C, 3), 31.0 (6C, 3), 34.6 (2C,
0), 62.5 (2C, 1), 127.4 (4C, 1), 127.8 (4C, 1), 128.0 (4C, 1), 128.2
(4C, 1), 134.1 (2C, 0), 136.3 (2C, 0), 138.8 (2C, 0), 155.0 (2C, 0).
Anal. Calcd for C38H48N2O4S2: C, 69.06; H, 7.32, N, 4.24. Found: C,
68.85; H, 7.19; N, 4.09.
(26) Rand, C. L.; Van Horn, D. E.; Moore, M. W.; Negishi, E. J. Org.
Chem. 1981, 46, 4096.
(27) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118,
2748.
(28) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(29) Dymock, B. W.; Kocienski, P. J.; Pons, J.-M. J. Chem. Soc.,
Chem. Commun. 1996, 1053.
We thank the EPSRC, Merck Sharpe & Dohme and Pfizer Central
Research for support through the Asymmetric Synthesis LINK
scheme and the Royal Society of Chemistry for a Journals Grant (J.-
M. P.). We also thank Professor Yves Langlois for details of his total
synthesis of 1233A prior to publication.
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