Formal synthesis of salinosporamide A using a nickel-catalyzed reductive aldol cyclization-lactonization as a key step

Article abstract of DOI:10.1016/j.tet.2008.06.038

Application of a sequential nickel-catalyzed reductive aldol cyclization-lactonization reaction in a short formal synthesis of salinsporamide A, a potent 20S proteasome inhibitor and anti-cancer compound, is described.

Full text of DOI:10.1016/j.tet.2008.06.038

Tetrahedron 64 (2008) 7896–7901
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Formal synthesis of salinosporamide A using a nickel-catalyzed reductive
aldol cyclization–lactonization as a key step
*
Isabel Villanueva Margalef, Leszek Rupnicki, Hon Wai Lam
School of Chemistry, University of Edinburgh, Joseph Black Building, The King’s Buildings, West Mains Road, Edinburgh EH9 3JJ, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 April 2008
Received in revised form 28 May 2008
Accepted 12 June 2008
Available online 14 June 2008
Application of a sequential nickel-catalyzed reductive aldol cyclization–lactonization reaction in a short
formal synthesis of salinsporamide A, a potent 20S proteasome inhibitor and anti-cancer compound, is
described.
Ó 2008 Elsevier Ltd. All rights reserved.
O
O
Et2Zn (2 equiv)
1. Introduction
PMP
Ni(acac)2 (5 mol %)
Me
EtO2C
N
EtO2C
N
THF/hexane
0 °C to rt
ð1Þ
Me
HO
Advances in transition-metal-catalyzed cyclization reactions
provide the means to access increasingly diverse carbocyclic and
heterocyclic compounds from relatively simple starting materials,
with often impressive levels of diastereo- and enantiose-
lectivity.1,2,3 Reductive cyclizations, where reaction is promoted by
stoichiometric reductants such as molecular hydrogen, silanes,
formic acid, stannanes, borohydrides or main-group organometal-
lic reagents, represent an important class of these trans-
formations.2,3 Many of these reactions have been developed to
a level of utility that enable their application in natural product
synthesis.4
PMP O
2
1
>19:1 dr
76%
O
O
O
Me
Me
Cl
Me
Me
Me
NH
NH
NH
2
2
3
5
3
5
Me
Me
OH
OH
OH
HO
O
O
S
O
O
O
NHAc
salinosporamide A (3) omuralide (4) lactacystin (5)
Our research in this area has led to the development of a series
of metal-catalyzed reductive aldol cyclization reactions that form
CO2H
b
-hydroxylactones and b-hydroxylactams in highly diaster-
eoselective fashion.5 A notable result is the cyclization of 1 using
Figure 1.
Ni(acac)2 as the precatalyst and Et2Zn as the stoichiometric re-
ductant, which provided
b-hydroxy-g-lactam 2 as a single dia-
stereomer (Eq. 1).5d,6 This outcome was of interest because
examination of the structure of 2 revealed similarities with the core
of salinosporamide A (3) (Fig. 1), a secondary metabolite isolated by
Fenical and co-workers from marine actinomycete bacteria of Sal-
inospora strain CNB-392.7 This compound has attracted significant
attention because of its impressive biological activity.7 Not only is 3
a highly potent inhibitor of the 20S proteasome, an abundant
complex within cells that plays an important role in the degrada-
tion and removal of misfolded proteins,8 it also exhibits promising
potential as an anti-cancer therapeutic agent. Indeed, 3 is currently
in clinical trials for this purpose.9
Structurally, salinosporamide A (3) shares its fused
-lactone bicyclic core with omuralide (4), a product derived
g-lactam-
b
from the terrestrial microbial metabolite lactacystin (5).10,11 Al-
though omuralide (4) is also an effective 20S proteasome in-
hibitor, differences between 3 and 4 at C2, C3 and C5 render 3
approximately 35 times more potent than 4.7 Salinosporamide A
(3) has also elicited significant interest from a synthetic per-
spective, with a number of total and partial syntheses having
been reported.11c,12
Given the huge interest in salinosporamide A (3), and the
resemblance of
b-hydroxy-g-lactam 2 to the core of 3, we be-
came interested in the possibility of applying our nickel-cata-
lyzed reductive aldol methodology5d in a synthetic route towards
this natural product. Strategically, construction of the g-lactam of
3 by formation of the C2–C3 bond has already been accom-
* Corresponding author. Tel.: þ44 131 650 4831; fax: þ44 131 650 6453.
E-mail address: h.lam@ed.ac.uk (H.W. Lam).
plished by Corey and co-workers (Scheme 1).12a,b In their original
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.038

I. Villanueva Margalef et al. / Tetrahedron 64 (2008) 7896–7901
7897
total synthesis of salinosporamide
A (3), acrylamide 6 was
NHPMB
OBn
cyclized in a Baylis–Hillman reaction13 (method A) to provide
g-
Me
Me
O
lactam 7 as a 9:1 mixture of diastereomers after 1 week.12a The
same group subsequently developed improved conditions for this
cyclization, involving the Kulinkovich reagent14 formed from
CO2Me
OH
10
EtO2C
EtO2C
OH
(COCl) , DMSO, Et3N
CH2Cl2,2-78 °C to -40 °C
72%
(COCl)2, DMF
CH2Cl2, 0 °C to rt
Ti(Oi-Pr)4 and cyclopentylmagnesium chloride (method B).12b
A
sequence of several steps including a tin hydride-mediated rad-
ical cyclization was then required to transform the exomethylene
group of 7 into the chloroethyl functionality of salinosporamide
A (3).12a
O
NHPMB
OBn
+
Cl
CO2Me
11
12
O
i-Pr2NEt, CH2Cl2
0 °C to rt
>99% (based on 11)
O
O
O
PMB
OBn
PMB
OBn
N
PMB
N
N
Method A 9:1 dr, 90%
Method B 99:1 dr, 83%
EtO2C
Me
OBn
Me
Me
CO2Me
HO CO2Me
7
O
CO2Me
6
O
8
Method A: quinuclidine, DME, 0 °C, 7 d.
Method B: (i) Ti(Oi-Pr)4, c-C5H9MgCl, t-BuOMe, -40 °C, 30 min,
then I2, -40 °C, 2 h, then 0 °C, 2 h.
Scheme 3. Preparation of substrate 8 for reductive aldol cyclization.
(ii) Et3N, CH2Cl2, rt, 30 min.
With 8 in hand, the crucial reductive aldol cyclization was
attempted (Table 1). Unfortunately, exposure of 8 to Ni(acac)2 and
Et2Zn (as in Eq.1)5d provided onlyan intractable mixture of products
(entry 1). The situationwas not improved upon replacing Et2Znwith
Et3Al5c (entry 2), or by replacing Ni(acac)2 with Co(acac)2$2H2O5c
(entries 3 and 4). The effect of phosphine ligands on the reactionwas
then examined. Although the combination of CoCl2 and DPPFoffered
no improvement (entry 5), it was found that commercially available
nickel–phosphine complexes were effective precatalysts. Using
(Ph3P)2NiBr2 (entry 6), none of the initially desired product 9 was
Scheme 1. Construction of g
-lactam 7 by Corey and co-workers.12a,b
Since the ethyl ester-containing side-chain in 2 can be converted
into the chloroethyl group of salinosporamide A (3) without further
carbon–carbon bond formation, we envisaged that a suitably more
functionalized variant of Eq. 1 might prove advantageous in a syn-
thetic route towards 3. Accordingly, a,b-unsaturated amide 8 be-
came a target for our investigations (Scheme 2).
isolated. Instead, fused
g-lactone-g-lactam 15 containing the
O
O
PMB
OBn
PMB
EtO2C
N
Ni(acac)2
Et2Zn
EtO2C
N
OBn
Me
Table 1
Me
CO2Me
Reductive aldol cyclization of 8
HO CO2Me
O
9
O
8
O
PMB
OBn
Cl
EtO2C
N
steps
NH
Me
Me
CO2Me
OH
O
O
O
8
salinosporamide A (3)
metal salt, reductant
THF, 0 °C to rt
Scheme 2. Reductive aldol cyclization strategy towards 3.
O
N
O
Compared with 1, substrate 8 possesses a more densely func-
tionalized, more sterically congested structure containing several
Lewis basic groups that could potentially bind the catalyst and
organometallic reductant and divert the course of the proposed
cyclization towards deleterious side reactions. Furthermore, we
would be reliant upon the single stereocenter present in 8 to
control the absolute configurations of the two new stereocenters
formed in the cyclization to provide 9 preferentially, and pre-
diction of the sense of diastereoselectivity (if any) was by no
means straightforward. Therefore, substrate 8 would provide
a challenging test for our methodology. In this article, we describe
the successful utilization of 8 in a formal synthesis of salinospor-
amide A (3).
PMB
OBn
PMB
OBn
EtO2C
EtO2C
+
EtZnO
N
Me
EtZnO CO2Me
Me CO2Me
13
14
Desired
Undesired
O
O
PMB
OBn
PMB
OBn
N
N
+
O
O
O
O
CO2Me
Me CO2Me
16
Me
15
Entry
Precatalyst
(10 mol %)
Reductant
(2 equiv)
Result/yields
1
2
3
4
Ni(acac)2
Ni(acac)2
Co(acac)2
Co(acac)2
CoCl2/DPPF
(Ph3P)2NiBr2
Et2Zn
Et3Al
Et2Zn
Et3Al
Et2Zn
Et2Zn
Et2Zn
Intractable mixture
Intractable mixture
<10% Conversion
Intractable mixture
Intractable mixture
35% of 15,a 30% of 16a
42% of 15,a 30% of 16a
2. Results and discussion
Cyclization precursor 8 was prepared in straightforward fash-
ion as illustrated in Scheme 3. Swern oxidation15 of the pre-
viously described amino alcohol 1012a provided aminoketone 11,
which was then acylated with the acid chloride 12 derived from
5
6
7b
(Me3P)2NiCl2
a
Isolated yield.
mono-ethyl fumarate16 to afford
yield.
a,b-unsaturated amide 8 in high
b
Initial reaction temperature of ꢀ15 ꢁC. DPPF¼1,10-bis(diphenylphosphino)-
ferrocene.

7898
I. Villanueva Margalef et al. / Tetrahedron 64 (2008) 7896–7901
desired stereochemistry was isolated in 35% yield, along with
a comparable amount of the alternative diastereomer 16, the ste-
reochemistry of which was established by X-ray crystallography.17
Marginally superior results were obtained using (Me3P)2NiCl2 at an
initial temperature of ꢀ15 ꢁC (entry 7). Attempts to increase the
diastereoselectivity of the reaction in favor of 15 by further modifi-
cation of the conditions have so far been unsuccessful.
3. Conclusion
Largely following the strategy of Corey and co-workers,12a
a concise formal synthesis of salinosporamide A (3) has been ach-
ieved. The distinguishing feature of the work described herein is
the use of a sequential nickel-catalyzed reductive aldol cyclization–
lactonization reaction of 8 to construct the g-lactam of 3. Although
The lactones 15 and 16 are produced presumably as a result of
the zinc alkoxides 13 and 14, formed upon reductive aldol reaction,
cyclizing onto the pendant ethyl esters. Although lactonization was
unexpected in light of the reaction shown in Eq. 1, it turned out to
be a useful bonus, since it conveniently protected the tertiary
alcohol towards subsequent transformations.18
the diastereoselectivity of this transformation remains to be im-
proved, this approach represents an attractive method to install the
C2 side-chain with simultaneous protection of the C5 oxygen, and
further demonstrates the utility of nickel catalysis in complex
molecule synthesis.1b,4a–c,f Further applications of our reductive
aldol cyclization methodology will be reported in due course.
The desired diastereomer 15 was subjected to palladium-cata-
lyzed debenzylation to provide alcohol 17 (84% yield) (Scheme 4).
X-ray crystallography of this compound allowed confirmation of its
stereochemistry, and hence that of its immediate precursor 15.17
Oxidation of 17 to aldehyde 18 in readiness for installation of the
cyclohexenyl group was accomplished using the Dess–Martin
periodinane.19 Aldehyde 18 proved to be somewhat unstable, and
was immediately reacted with 2-cyclohexenylzinc chloride (19) as
described by Corey and co-workers12a to give homoallylic alcohol
20 in highly selective fashion (one observable diastereomer by 1H
NMR analysis). X-ray crystallography of 20 showed that the desired
stereochemistry had been obtained in the allylation.17 Finally, re-
ductive ring-opening of the lactone in 20 was accomplished using
NaBH4 to give triol 21, the conversion of which into salinospor-
amide A (1) has already been described by the groups of Corey12a
and Pattenden.12d
4. Experimental section
4.1. General
All non-aqueous reactions were carried out under a nitrogen
atmosphere in oven-dried apparatus. CH2Cl2 and THF were dried
and purified by passage through activated alumina columns using
a solvent purification system from www.glasscontoursolventsys-
tems.com. ‘Petrol’ refers to that fraction of light petroleum ether
boiling in the range 40–60 ꢁC. Commercially available CoCl2 was
dried by heating under vacuum until it turned from purple to blue.
All other commercially available reagents were used as received.
Thin layer chromatography (TLC) was performed on Merck DF-
Alufoilien 60F254 0.2 mm precoated plates. Product spots were vi-
sualized by UV light at 254 nm, and subsequently developed using
potassium permanganate or ceric ammonium molybdate solution
as appropriate. Flash column chromatography was carried out us-
ing silica gel (Fisher Scientific 60 Å particle size 35–70 mm). Melting
points were recorded on a Gallenkamp melting point apparatus and
are uncorrected. Infra-red spectra were recorded on a Jasco FT/IR-
460 Plus instrument as a thin film on sodium chloride plates or as
a dilute solution in CHCl3. 1H NMR spectra were recorded on
a Bruker DPX360 (360 MHz) spectrometer or a Bruker ARX250
O
O
PMB
OBn
PMB
OH
N
N
H2, Pd/C
O
O
O
EtOH, rt
84%
O
O
O
(250 MHz) spectrometer. Chemical shifts (d) are quoted in parts per
CO2Me
CO2Me
Me
17
Me
15
million (ppm) downfield of tetramethylsilane, using residual pro-
tonated solvent as internal standard (CDCl3 at 7.27 ppm). Abbre-
viations used in the description of resonances are: s (singlet),
d (doublet), t (triplet), q (quartet), app (apparent) and br (broad).
Coupling constants (J) are quoted to the nearest 0.1 Hz. Proton-
decoupled 13C NMR spectra were recorded on a Bruker ARX250
O
PMB
N
CHO
Dess-Martin
periodinane
CH2Cl2, rt
CO2Me
Me
18
(62.9 MHz) spectrometer. Chemical shifts (d) are quoted in parts per
THF, -78 °C
ZnCl
61% (two steps)
million (ppm) downfield of tetramethylsilane, using deuterated
solvent as internal standard (CDCl3 at 77.0 ppm). Assignments were
made using the DEPT sequence with secondary pulses at 90ꢁ and
135ꢁ. High resolution mass spectra were recorded on a Finnigan
MAT 900 XLT spectrometer using the electrospray (ES) positive ion
mode at the EPSRC National Mass Spectrometry Service Centre,
University of Wales, Swansea, or on a Finnigan MAT 900 XLT
spectrometer or a Kratos MS50TC spectrometer at the School of
Chemistry, University of Edinburgh. Optical rotations were per-
formed on an Optical Activity POLAAR 20 polarimeter.
19
O
O
HO
NPMB
NPMB
NaBH4
Me
HO
O
MeOH, rt
60%
O
OH
OH
Me
CO2Me
21
CO2Me
20
Four steps
(Ref. 12a and 12d)
O
4.1.1. (R)-Methyl 2-benzyloxymethyl-2-(4-methoxybenzylamino)-
3-oxobutanoate (11)
Cl
NH
Me
To a stirred solution of (COCl)2 (1.67 mL, 18.8 mmol) in CH2Cl2
(40 mL) at ꢀ78 ꢁC was added DMSO (2.70 mL, 37.6 mmol) dropwise
over 3 min. After stirring for 15 min, a solution of the alcohol 1012a
(3.34 g, 8.94 mmol) in CH2Cl2 (30 mL) was added via cannula over
5 min. The reaction mixture was stirred at ꢀ78 ꢁC for 1 h and Et3N
(5.23 mL, 37.6 mmol) was then added over 1 min. The reaction
mixture was stirred at ꢀ78 ꢁC for 1 h, allowed to warm to ꢀ40 ꢁC
over 2 h, and then quenched with saturated aqueous NH4Cl
OH
O
O
salinosporamide A (3)
Scheme 4. Completion of the formal synthesis of 3.

I. Villanueva Margalef et al. / Tetrahedron 64 (2008) 7896–7901
7899
solution (40 mL). The aqueous layer was separated and extracted
with CH2Cl2 (3ꢂ20 mL) and the combined organic layers were
dried (MgSO4) and concentrated in vacuo. Purification of the resi-
due by column chromatography (10% EtOAc/petrol/20% EtOAc/
a white solid. Recrystallization of 16 from EtOAc/petrol gave col-
orless blocks that were suitable for X-ray crystallography.
25
Data for 15: Rf¼0.19 (30% EtOAc/CHCl3); [
a]
ꢀ33.3 (c 1.02,
D
CHCl3); IR (film) 2955, 1789 (C]O), 1733 (C]O), 1699 (C]O), 1612,
1513, 1439, 1404, 1248, 1178, 1129, 736 cmꢀ1 1H NMR (250 MHz,
CDCl3) 7.35–7.25 (5H, m, ArH), 7.12–7.08 (2H, m, ArH), 6.60 (2H,
petrol) gave the ketone 11 (2.39 g, 72%) as a pale yellow solid.
;
25
Rf¼0.55 (30% EtOAc/hexane); mp 60–62 ꢁC; [
a
]
D
ꢀ12.7 (c 1.02,
d
CHCl3); IR (CHCl3) 3347 (NH), 2952, 2836, 1741 (C]O), 1718 (C]O),
dm, J¼8.7 Hz, ArH), 5.05 (1H, d, J¼15.2 Hz, CH2Ar), 4.28 (1H, d,
J¼15.2 Hz, CH2Ar), 3.91 (1H, d, J¼11.5 Hz, CH2O), 3.83 (1H, d,
J¼10.4 Hz, CH2O), 3.81 (1H, d, J¼11.5 Hz, CH2O), 3.81 (3H, s, OCH3),
3.74 (3H, s, OCH3), 3.21 (1H, d, J¼10.4 Hz, CH2O), 3.05 (1H, dd, J¼9.3,
1.5 Hz, CH2CH), 2.96 (1H, dd, J¼18.3, 1.5 Hz, CH2CH), 2.79 (1H, dd,
J¼18.3, 9.3 Hz, CH2CH), 1.61 (3H, s, CH3CO); 13C NMR (62.9 MHz,
1511, 1245, 1178, 1033, 700 cmꢀ1; 1H NMR (250 MHz, CDCl3)
d 7.39–
7.28 (5H, m, ArH), 7.25 (2H, dm, J¼8.7 Hz, ArH), 6.85 (2H, dm,
J¼8.7 Hz, ArH), 4.59 (1H, d, J¼12.4 Hz, CH2Ar), 4.53 (1H, d,
J¼12.4 Hz, CH2Ar), 4.02 (1H, d, J¼10.1 Hz, CH2Ar), 3.90 (1H, d, J¼
10.1 Hz, CH2Ar), 3.80 (3H, s, OCH3), 3.74 (3H, s, OCH3), 3.59 (1H, d,
J¼12.3 Hz, CH2OBn), 3.46 (1H, d, J¼12.3 Hz, CH2OBn), 2.53 (1H, br s,
CDCl3)
d 173.5 (C), 172.9 (C), 166.9 (C), 158.9 (C), 136.7 (C), 130.0
NH), 2.21 (3H, s, COCH3); 13C NMR (62.9 MHz, CDCl3)
d
203.3 (C),
(2ꢂCH), 129.4 (C), 128.5 (2ꢂCH), 127.9 (CH), 127.3 (2ꢂCH), 113.6
(2ꢂCH), 88.5 (C), 75.8 (C), 72.8 (CH2), 67.7 (CH2), 55.2 (CH3), 52.8
(CH3), 47.5 (CH), 45.1 (CH2), 30.7 (CH2), 19.4 (CH3); HRMS (ES) exact
169.8 (C), 158.7 (C), 137.6 (C), 131.7 (C), 129.4 (2ꢂCH), 128.4 (2ꢂCH),
127.8 (3ꢂCH), 113.7 (2ꢂCH), 74.9 (C), 73.5 (CH2), 68.1 (CH2), 55.3
(CH3), 52.7 (CH3), 46.7 (CH2), 25.7 (CH3); HRMS (ES) exact mass
calcd for C21H26NO5 [MþH]þ: 372.1805, found: 372.1804.
mass calcd for C25H28NO7 [MþH]þ: 454.1860, found: 454.1856.
25
Data for 16: Rf¼0.08 (30% EtOAc/CHCl3); mp 105–106 ꢁC; [
a]
D
ꢀ17.9 (c 1.01, CHCl3); IR (film) 2952, 2870, 1789 (C]O), 1743 (C]O),
4.1.2. (R)-Ethyl (E)-3-[N-(1-benzyloxymethyl-1-carbomethoxy-2-
1703 (C]O), 1613, 1512, 1434, 1246, 1128, 739 cmꢀ1
;
1H NMR
oxopropyl)-N-(4-methoxybenzyl)carbamoyl]acrylate (8)
(250 MHz, CDCl3) 7.34–7.28 (3H, m, ArH), 7.22–7.19 (2H, m, ArH),
d
To
a
stirred solution of mono-ethyl fumarate16 (858 mg,
7.09 (2H, dm, J¼8.8 Hz, ArH), 6.78 (2H, d, J¼8.8 Hz, ArH), 4.68 (1H, d,
J¼15.2 Hz, CH2Ar), 4.37 (1H, d, J¼15.2 Hz, CH2Ar), 4.30 (1H, d, J¼
11.7 Hz, CH2Ar), 4.23 (1H, d, J¼11.7 Hz, CH2Ar), 3.90 (1H, d,
J¼10.2 Hz, CH2OBn), 3.78 (3H, s, OCH3), 3.71 (1H, d, J¼10.2 Hz,
CH2OBn), 3.64 (3H, s, OCH3), 3.03 (1H, dd, J¼9.7, 1.9 Hz, CH2CH),
3.00 (1H, dd, J¼18.3, 1.9 Hz, CH2CH), 2.84 (1H, dd, J¼18.3, 9.7 Hz,
5.65 mmol) in CH2Cl2 (10 mL) at 0 ꢁC was added (COCl)2 (0.56 mL,
6.40 mmol) followed by DMF (one drop). The resulting mixture was
stirredfor 1 h at roomtemperature, and then transferredvia cannula
to a solution of the amine 11 (1.33 g, 3.60 mmol) and i-Pr2NEt
(1.10 mL, 6.40 mmol) in CH2Cl2 (10 mL) at 0 ꢁC. The reaction mixture
was stirred at 0 ꢁC for 10 min and then at room temperature for 18 h,
when it was quenched with saturated aqueous NH4Cl solution
(20 mL). The aqueous layer was separated and extracted with CH2Cl2
(3ꢂ20 mL), and the combined organic layers were dried (MgSO4),
filtered and concentrated in vacuo. Purification of the residue by
CH2CH), 1.47 (3H, s, CH3CO); 13C NMR (62.9 MHz, CDCl3)
d 173.4 (C),
173.2 (C), 169.2 (C), 158.7 (C), 137.1 (C), 129.2 (2ꢂCH), 129.0 (C),
128.3 (2ꢂCH), 127.7 (3ꢂCH), 113.6 (2ꢂCH), 86.6 (C), 75.3 (C), 73.6
(CH2), 68.7 (CH2), 55.2 (CH3), 52.8 (CH3), 46.9 (CH), 45.1 (CH2), 30.9
(CH2), 21.8 (CH3); HRMS (ES) exact mass calcd for C25H28NO7
[MþH]þ: 454.1860, found: 454.1858.
column chromatography (20% EtOAc/petrol) gave the amide 8
25
(1.79 g, >99%) as a pale yellowoil. Rf¼0.45 (30% EtOAc/hexane); [
a]
D
ꢀ18.2 (c 1.18, CHCl3); IR (film) 2953, 2837, 1722 (C]O), 1658 (C]O),
1513, 1408, 1294, 1248, 1175, 1032, 974, 822 cmꢀ1 1H NMR
(360 MHz, CDCl3)
7.35–7.27 (5H, m, ArH), 7.21 (1H, d, J¼15.3 Hz,
4.1.4. (3aR,6R,6aS)-6-Hydroxymethyl-5-(4-methoxybenzyl)-6a-
methyl-2,4-dioxohexahydrofuro[2,3-c]pyrrole-6-carboxylic acid
methyl ester (17)
;
d
]CH), 7.14–7.11 (2H, m, ArH), 6.91 (2H, dm, J¼8.8 Hz, ArH), 6.82 (1H,
d, J¼15.3 Hz, ]CH), 4.94 (1H, d, J¼18.3 Hz, CH2Ar), 4.79 (1H, d,
J¼18.3 Hz, CH2Ar), 4.31 (1H, d, J¼11.9 Hz, CH2Ar), 4.27 (1H, d,
J¼11.9 Hz, CH2Ar), 4.18 (2H, q, J¼7.1 Hz, OCH2CH3), 3.82 (3H, s, OCH3),
3.80 (3H, s, OCH3), 3.76 (2H, br s, CH2OBn), 2.43 (3H, s, CH3C]O),1.25
A mixture of benzyl ether 15 (354 mg, 0.78 mmol) and 10% Pd/C
(99 mg, 0.093 mmol) in EtOH (5 mL) at room temperature was
evacuated and flushed with H2 (three times) and then stirred vig-
orously under an atmosphere of H2 (1 atm, H2 balloon) at room
temperature for 18 h. The reaction mixture was filtered through
Celite and concentrated in vacuo. Purification of the residue by
column chromatography (50% EtOAc/petrol) gave the alcohol 17
(240 mg, 84%) as a white powder. Recrystallization of 17 from
(3H, t, J¼7.1 Hz, OCH2CH3); 13C NMR (62.9 MHz, CDCl3)
d 197.6 (C),
168.0 (C), 167.5 (C), 165.2 (C), 158.9 (C), 136.5 (C), 133.3 (CH), 133.1
(CH),129.7 (C),128.4 (2ꢂCH),127.9 (CH),127.5 (2ꢂCH),127.1 (2ꢂCH),
114.1 (2ꢂCH), 77.5 (C), 73.7 (CH2), 70.1 (CH2), 61.1 (CH2), 55.2 (CH3),
52.9 (CH3), 48.9 (CH2), 27.9 (CH3), 14.0 (CH3); HRMS (ES) exact mass
calcd for C27H32NO8 [MþH]þ: 498.2122, found: 498.2123.
CH2Cl2/Et2O gave colorless blocks that were suitable for X-ray
25
crystallography. Rf¼0.52 (100% EtOAc); mp 144–146 ꢁC; [
a]
ꢀ30.1
D
(c 0.95, CHCl3); IR (CHCl3) 3437 (OH), 2955, 2837, 2253, 1787
(C]O), 1757 (C]O), 1692 (C]O), 1613, 1513, 1247, 1035, 951, 914,
4.1.3. (3aR,6R,6aS)-6-Benzyloxymethyl-5-(4-methoxybenzyl)-6a-
methyl-2,4-dioxohexahydrofuro[2,3-c]pyrrole-6-carboxylic acid
methyl ester (15) and (3aS,6R,6aR)-6-benzyloxymethyl-5-(4-
methoxybenzyl)-6a-methyl-2,4-dioxohexahydrofuro[2,3-c]pyrrole-
6-carboxylic acid methyl ester (16)
731 cmꢀ1; 1H NMR (250 MHz, CDCl3)
d
7.37 (2H, dm, J¼8.6 Hz, ArH),
6.87 (2H, dm, J¼8.6 Hz, ArH), 5.22 (1H, d, J¼15.2 Hz, NCH2), 4.24
(1H, d, J¼15.2 Hz, NCH2), 3.95 (1H, dd, J¼13.0, 8.9 Hz, CH2OH), 3.83
(3H, s, OCH3), 3.80 (3H, s, OCH3), 3.43 (1H, dd, J¼13.0, 5.5 Hz,
CH2OH), 3.04 (1H, dd, J¼9.1, 1.7 Hz, CH2CH), 2.96 (1H, dd, J¼18.1,
1.7 Hz, CH2CH), 2.85 (1H, dd, J¼18.1, 9.1 Hz, CH2CH), 1.69 (3H, s,
A solution of a,b-unsaturated amide 8 (875 mg, 1.76 mmol) and
(Me3P)2NiCl2 (115 mg, 0.175 mmol) in THF (75 mL) was stirred at
room temperature for 30 min and then cooled to ꢀ15 ꢁC (ice/salt
bath). Et2Zn (3.52 mL, 1 M solution in THF, 3.52 mmol) was then
added over 0.5 min. The reaction mixture was allowed to warm
slowly to room temperature over 18 h, and then quenched carefully
with saturated aqueous NH4Cl solution (50 mL) and extracted with
EtOAc (3ꢂ30 mL). The combined organic layers were dried (MgSO4)
and concentrated in vacuo. Purification of the residue by column
chromatography (20% EtOAc/petrol/35% EtOAc/petrol) gave the
double cyclization product 15 (354 mg, 42%) as a pale yellow oil,
followed by the double cyclization product 16 (253 mg, 30%) as
CH3CO); 13C NMR (62.9 MHz, CDCl3)
d 173.7 (C), 172.7 (C), 167.1 (C),
159.5 (C), 129.6 (2ꢂCH and C), 114.6 (2ꢂCH), 88.3 (C), 77.3 (C), 60.9
(CH2), 55.3 (CH3), 52.8 (CH3), 47.6 (CH), 44.9 (CH2), 30.5 (CH2), 19.8
(CH3); HRMS (ES) exact mass calcd for C18H25N2O7 [MþNH4]þ:
381.1656, found: 381.1660.
4.1.5. (3aR,6R,6aS)-6-Formyl-5-(4-methoxybenzyl)-6a-methyl-
2,4-dioxohexahydrofuro[2,3-c]pyrrole-6-carboxylic acid methyl
ester (18)
To a solution of the alcohol 17 (30 mg, 0.082 mmol) in CH2Cl2
(0.8 mL) at room temperature was added Dess–Martin periodinane

7900
I. Villanueva Margalef et al. / Tetrahedron 64 (2008) 7896–7901
(43 mg, 0.099 mmol). The reaction mixture was stirred for 1.5 h,
quenched with H2O (5 mL) and extracted with EtOAc (3ꢂ10 mL).
The combined organic layers were dried (Na2SO4) and concentrated
in vacuo to leave the aldehyde 18 as a pale yellow oil. This aldehyde
was not very stable and was generally used immediately in the next
step without purification. On one occasion, purification of a small
amount of crude product by column chromatography (50% EtOAc/
petrol) was performed for characterization purposes. Rf¼0.34 (100%
EtOAc); IR (CHCl3) 2956, 1788 (C]O), 1760 (C]O), 1728 (C]O),
(CHCl3) 3331 (OH), 2925, 2853, 1752 (C]O), 1670 (C]O), 1512,
1441, 1245, 1175, 1034, 801 cmꢀ1; 1H NMR (250 MHz, CDCl3)
7.30
d
(2H, dm, J¼8.8 Hz, ArH), 6.85 (2H, dm, J¼8.8 Hz, ArH), 5.97–5.91
(1H, m, ]CH), 5.65–5.60 (1H, m, ]CH), 4.77 (1H, d, J¼15.2 Hz,
NCH2), 4.58 (1H, d, J¼15.2 Hz, NCH2), 4.15 (1H, app t, J¼6.3 Hz,
CHOH), 3.87–3.81 (1H, m, CH2OH), 3.80–3.75 (1H, m, CH2OH), 3.79
(3H, s, OCH3), 3.71 (3H, s, OCH3), 3.02 (1H, dd, J¼8.1, 4.8 Hz,
CHC]O), 2.20 (1H, br s, CHCHOH), 2.01 (2H, br s, (CH2)3 and/or
CH2CH2OH), 1.93–1.78 (2H, m, (CH2)3 and/or CH2CH2OH), 1.76–1.65
(4H, m, (CH2)3 and/or CH2CH2OH), 1.64 (3H, s, CH3CO), 1.54–1.41
(2H, m, (CH2)3 and/or CH2CH2OH); 13C NMR (62.9 MHz, CDCl3)
1687 (C]O), 1513, 1438, 1246, 1176, 949 cmꢀ1
CDCl3)
;
1H NMR (250 MHz,
d
9.47 (1H, s, CHO), 7.05 (2H, dm, J¼8.7 Hz, ArH), 6.81 (2H,
dm, J¼8.7 Hz, ArH), 4.86 (1H, d, J¼14.4 Hz, NCH2), 4.39 (1H, d,
J¼14.4 Hz, NCH2), 3.90 (3H, s, OCH3), 3.78 (3H, s, OCH3), 3.08 (1H,
dd, J¼9.7, 1.8 Hz, CH2CH), 2.99 (1H, dd, J¼18.4, 1.8 Hz, CH2CH), 2.85
(1H, dd, J¼18.4, 9.7 Hz, CH2CH), 1.52 (3H, s, CH3CO); 13C NMR
d
178.5 (C), 169.7 (C), 158.2 (C), 132.9 (CH), 130.2 (C), 128.0 (2ꢂCH),
124.8 (CH), 113.7 (2ꢂCH), 81.8 (C), 80.6 (C), 77.2 (CH), 61.7 (CH2),
55.2 (CH3), 51.9 (CH), 51.3 (CH3), 47.8 (CH2), 38.6 (CH), 28.2 (CH2),
26.8 (CH2), 25.0 (CH2), 21.2 (CH3), 20.6 (CH2); HRMS (ES) exact mass
calcd for C24H33NO7Na [MþNa]þ: 470.2149, found: 470.2150.
Interestingly, the NMR data we obtained for triol 21 (recorded
above) displayed subtle but appreciable differences to those
reported by Corey and co-workers for the same compound,12a most
notably in the 13C NMR chemical shifts. However, we have also
obtained from Pattenden and co-workers copies of the NMR
spectra for the same compound that was prepared in their total
synthesis of salinosporamide A,12d and our 13C NMR data are a good
match for theirs (13C NMR spectrum supplied by Pattenden in
Supplementary data). The most likely explanation for this obser-
vation is that the values of the 13C NMR chemical shifts for triol 21
are concentration-dependent; both our and the Pattenden group’s
13C NMR spectra were run at relatively low concentration, whereas
the Corey group’s 13C NMR spectrum was run at relatively high
concentration. Due to limited quantities of triol 21, we were unable
to verify this hypothesis.
(62.9 MHz, CDCl3)
d 195.5 (CH), 172.7 (C), 172.0 (C), 165.7 (C), 159.6
(C), 131.1 (2ꢂCH), 126.8 (C), 114.2 (2ꢂCH), 87.3 (C), 79.0 (C), 55.2
(CH3), 53.4 (CH3), 46.8 (CH), 45.6 (CH2), 30.7 (CH2), 20.5 (CH3);
LRMS (ES) 384 [MþNa]þ.
4.1.6. (3aR,6R,6aS)-6-[(S)-{(S)-Cyclohex-2-eny}hydroxymethyl]-5-
(4-methoxybenzyl)-6a-methyl-2,4-dioxohexahydrofuro [2,3-
c]pyrrole-6-carboxylic acid methyl ester (20)
To a solution of cyclohexenyltributyltin (19)20 (ca. 85% pure by
1H NMR analysis, 90 mg, 0.21 mmol) in THF (0.6 mL) at ꢀ78 ꢁC was
added n-BuLi (130 mL, 1.6 M solution in hexanes, 0.21 mmol). After
stirring at ꢀ78 ꢁC for 1 h, ZnCl2 (420
mL, 0.5 M solution in THF,
0.21 mmol) was added and stirring was continued at this temper-
ature for another 1 h. A solution of the unpurified aldehyde 18 from
the above experiment (theoretically 0.082 mmol) in THF (0.4 mL)
was then added via cannula, and after stirring for 3 h at ꢀ78 ꢁC, the
reaction was quenched with H2O (5 mL) and extracted with EtOAc
(3ꢂ5 mL). The combined organic layers were dried (MgSO4) and
concentrated in vacuo, and purification of the residue by column
chromatography (50% EtOAc/petrol) gave the homoallylic alcohol 20
(22.4 mg, 61% over two steps) as a white solid. Recrystallization
from 20 from a mixture of EtOAc/hexane and acetone (a few drops)
Acknowledgements
This work was supported by the EPSRC (GR/T07466/01) and the
European Commission (Project No. MEST-CT-2005-020744). We
thank Professor Gerald Pattenden at the University of Nottingham
and Professor Elias J. Corey at Harvard University for helpful dis-
cussions. In addition, we thank Professor Pattenden and Dr. Leleti
Rajender Reddy (Corey group) for providing copies of 1H NMR and
13C NMR spectra of triol 21. We are grateful to Professor Simon
Parsons, Dr. Anna Collins and Laura E. Budd at the School of
Chemistry, University of Edinburgh for assistance with X-ray crys-
tallography. The EPSRC National Mass Spectrometry Service Centre
at the University of Wales, Swansea is thanked for providing high
resolution mass spectra.
gave colorless needles that were suitable for X-ray diffraction.
25
Rf¼0.61 (100% EtOAc); mp 114–116 ꢁC; [
a]
þ3.0 (c 1.47, CHCl3); IR
D
(CHCl3) 3438 (OH), 2931, 2359, 1790 (C]O), 1755 (C]O), 1687
(C]O),1512, 1440, 1246, 1175, 807 cmꢀ1; 1H NMR (360 MHz, CDCl3)
d
7.19 (2H, dm, J¼8.7 Hz, ArH), 6.84 (2H, dm, J¼8.7 Hz, ArH), 5.92
(1H, dm, J¼10.3 Hz, ]CH), 5.68 (1H, dm, J¼10.3 Hz, ]CH), 4.80 (1H,
d, J¼14.9 Hz, NCH2), 4.54 (1H, d, J¼14.9 Hz, NCH2), 4.13 (1H, t,
J¼7.1 Hz, CHOH), 3.78 (6H, s, 2ꢂOCH3), 3.13 (1H, dd, J¼6.8, 3.3 Hz,
CH2CHC]O), 2.92 (1H, br s, OH), 2.82–2.80 (2H, m, CH2CHC]O),
2.32 (1H, br s, CHCHOH), 2.02 (2H, br s, (CH2)3), 1.81 (3H, s, CH3CO),
1.76–1.66 (2H, m, (CH2)3), 1.57–1.46 (1H, m, (CH2)3), 1.44–1.33 (1H,
Supplementary data
m, (CH2)3); 13C NMR (62.9 MHz, CDCl3)
d 174.8 (C), 173.0 (C), 167.8
(C), 158.3 (C), 131.8 (CH), 129.3 (C), 127.6 (2ꢂCH), 125.2 (CH), 113.7
(2ꢂCH), 91.1 (C), 79.0 (C), 76.9 (CH), 55.2 (CH3), 52.4 (CH3), 47.9
(CH2), 47.8 (CH), 38.3 (CH), 30.9 (CH2), 27.0 (CH2), 24.9 (CH2), 20.6
(CH2), 19.6 (CH3); HRMS (ES) exact mass calcd for C24H33N2O7
[MþNH4]þ: 461.2282, found: 461.2283.
1
Copies of H and 13C NMR spectra for new compounds, and 13
C
NMR spectrum of triol 21 supplied by Pattenden and co-workers.
Supplementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2008.06.038.
References and notes
4.1.7. (2R,3S,4R)-2-[(S)-{(S)-Cyclohex-2-enyl}hydroxymethyl]-3-
hydroxy-4-(2-hydroxyethyl)-1-(4-methoxybenzyl)-3-methyl-5-
oxopyrrolidine-2-carboxylic acid methyl ester (21)12a
To a solution of the lactone 20 (19.3 mg, 0.043 mmol) in MeOH
(0.6 mL) at room temperature was added NaBH4 (75 mg, 2.0 mmol)
portionwise over 2 min. The solution was stirred for 18 h, quenched
with H2O (4 mL) and extracted with EtOAc (3ꢂ4 mL). The combined
organic layers were dried (Na2SO4) and concentrated in vacuo.
Purification of the residue by column chromatography (70% EtOAc/
ˆ
1. For relevant reviews, see: (a) Michelet, V.; Toullec, P. Y.; Genet, J.-P. Angew.
Chem., Int. Ed. 2008, 47, 4268–4315; (b) Montgomery, J. Angew. Chem., Int. Ed.
2004, 43, 3890–3908; (c) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103,
2945–2964; (d) Aubert, C.; Buisine, O.; Malacria, M. Chem. Rev. 2002, 102, 813–
834; (e) Negishi, E.; Cope´ret, C.; Ma, S.; Liou, S.-Y.; Liu, F. Chem. Rev. 1996, 96,
365–393; (f) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. Rev. 1996,
96, 635–662.
2. Broene, R. D. Top. Curr. Chem. 2007, 279, 209–248.
3. For reviews of catalytic reductive aldol reactions, see: (a) Nishiyama, H.;
Shiomi, T. Top. Curr. Chem. 2007, 279, 105–137; (b) Jang, H.-Y.; Krische, M. J. Eur.
J. Org. Chem. 2004, 3953–3958; (c) Jang, H.-Y.; Krische, M. J. Acc. Chem. Res.
2004, 37, 653–661; (d) Huddleston, R. R.; Krische, M. J. Synlett 2003, 12–21; (e)
petrol) gave the triol 21 (11.7 mg, 60%) as a white foam. Rf¼0.12
25
(70% EtOAc/CHCl3); mp 83–84 ꢁC; [
a
]
þ3.5 (c 0.565, CHCl3); IR
D

I. Villanueva Margalef et al. / Tetrahedron 64 (2008) 7896–7901
7901
Chiu, P. Synthesis 2004, 2210–2215; (f) Motherwell, W. B. Pure Appl. Chem. 2002,
74, 135–142.
11. For reviews of synthetic efforts towards omuralide and lactacystin, see: (a)
Corey, E. J.; Li, W.-Z. D. Chem. Pharm. Bull. 1999, 47, 1–10; (b) Masse, C. E.;
Morgan, A. J.; Adams, J.; Panek, J. S. Eur. J. Org. Chem. 2000, 2513–2528; (c)
Shibasaki, M.; Kanai, M.; Fukuda, N. Chem. Asian. J. 2007, 2, 20–38.
12. (a) Reddy, L. R.; Saravanan, P.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 6230–
6231; (b) Reddy, L. R.; Fournier, J.-F.; Reddy, B. V. S.; Corey, E. J. Org. Lett. 2005, 7,
2699–2701; (c) Endo, A.; Danishefsky, S. J. J. Am. Chem. Soc. 2005, 127, 8298–
8299; (d) Mulholland, N. P.; Pattenden, G.; Walters, I. A. S. Org. Biomol. Chem.
2006, 4, 2845–2846; (e) Caubert, V.; Langlois, N. Tetrahedron Lett. 2006, 47,
4473–4475; (f) Caubert, V.; Masse´, J.; Retailleau, P.; Langlois, N. Tetrahedron Lett.
2007, 48, 381–384; (g) Ma, G.; Nguyen, H.; Romo, D. Org. Lett. 2007, 9, 2143–
2146; (h) Ling, T.; Macherla, V. R.; Manam, R. R.; McArthur, K. A.; Potts, B. C. Org.
Lett. 2007, 9, 2289–2292; For the synthesis of an omuralide–salinosporamide
hybrid, see: (i) Reddy, L. R.; Fournier, J.-F.; Reddy, B. V. S.; Corey, E. J. J. Am. Chem.
Soc. 2005, 127, 8974–8976.
4. For representative examples, see: (a) Chrovian, C. C.; Knapp-Reed, B.; Mont-
gomery, J. Org. Lett. 2008, 10, 811–814; (b) Woodwin, K. S.; Jamison, T. F. J. Org.
Chem. 2007, 72, 7451–7454; (c) Colby, E. A.; O’Brien, K. C.; Jamison, T. F. J. Am.
Chem. Soc. 2005, 127, 4297–4307; (d) Oh, C. H.; Rhim, C. Y.; Kim, M.; Park, D. I.;
Gupta, A. K. Synlett 2005, 2694–2696; (e) Trost, B. M.; Chung, C. K.; Pinkerton,
A. B. Angew. Chem., Int. Ed. 2004, 43, 4327–4329; (f) Tang, X.-Q.; Montgomery, J.
J. Am. Chem. Soc. 2000, 122, 6950–6954; (g) Trost, B. M.; Fleitz, F. J.; Watkins,
W. J. J. Am. Chem. Soc. 1996, 118, 5146–5147; (h) Yamada, H.; Aoyagi, S.;
Kibayashi, C. Tetrahedron Lett. 1996, 37, 8787–8790; (i) Trost, B. M.; Edstrom, E. D.
Angew. Chem., Int. Ed. Engl. 1990, 29, 520–522.
5. (a) Lam, H. W.; Joensuu, P. M. Org. Lett. 2005, 7, 4225–4228; (b) Lam, H. W.;
Murray, G. J.; Firth, J. D. Org. Lett. 2005, 7, 5743–5746; (c) Lam, H. W.; Joensuu,
P. M.; Murray, G. J.; Fordyce, E. A. F.; Prieto, O.; Luebbers, T. Org. Lett. 2006, 8,
3729–3732; (d) Joensuu, P. M.; Murray, G. J.; Fordyce, E. A. F.; Luebbers, T.; Lam,
H. W. J. Am. Chem. Soc. 2008, 130, 7328–7338.
13. (a) Baylis, A. B.; Hillman, M. E. D. Offenlegungsschrift 2155113, 1972; Chem.
Abstr. 1972, 34174q; For reviews, see: (b) Langer, P. Angew. Chem., Int. Ed. 2000,
39, 3049–3052; (c) Ciganek, E. Org. React. 1997, 51, 201–350; (d) Basavaiah, D.;
Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001–8062; (e) Drewes, S. E.; Roos,
G. H. P. Tetrahedron 1988, 44, 4653–4670.
6. For nickel-catalyzed reductive aldol reactions, see: Chrovian, C. C.; Mont-
gomery, J. Org. Lett. 2007, 9, 537–540. For a review of nickel-catalyzed reductive
cyclizations and couplings, see Ref. 1b.
7. Feling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C. A.; Jensen, P. R.; Fenical,
W. Angew. Chem., Int. Ed. 2003, 42, 355–357.
14. (a) Kulinkovich, O. G. Chem. Rev. 2003, 103, 2597–2632; (b) Sato, F.; Okamoto, S.
Adv. Synth. Catal. 2001, 343, 759–784.
8. (a) Fenteany, G. A.; Standaert, R. F.; Reichard, G. A.; Corey, E. J.; Schreiber, S. L.
Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 3358–3362; (b) Fenteany, G.; Standaert, R. F.;
Lane, W. S.; Choi, S.; Corey, E. J.; Schreiber, S. L. Science 1995, 268, 726–731.
9. (a)Chauhan,D.;Catley, L.;Li,G.;Podar, K.;Hideshima, T.;Velankar, M.;Mitsiades, C.;
Mitsiades, N.; Yasui, H.; Letai, A.; Ovaa, H.; Berkers, C.; Nicholson, B.; Chao, T.-H.;
Neuteboom, S. T. C.; Richardson, P.; Palladino, M. A.; Anderson, K. C. Cancer Cell
2005, 8, 407–419; (b) Macherla, V. R.; Mitchell, S. S.; Manam, R. R.; Reed, K. A.; Chao,
T.-H.;Nicholson, B.;Deyanat-Yazdi, G.;Mai, B.;Jensen, P. R.;Fenical,W.;Neuteboom,
S. T. C.; Lam, K. S.; Palladino, M. A.; Potts, B. C. M. J. Med. Chem. 2005, 48, 3684–3687;
(c) Joazeiro, C. A. P.; Anderson, K. C.; Hunter, T. Cancer Res. 2006, 66, 7840–7842.
10. Lactacystin isolation papers: (a) Omura, S.; Fujimoto, T.; Otoguro, K.; Matsuzaki,
K.; Moriguchi, R.; Tanaka, H.; Saski, Y. J. Antibiot. 1991, 44, 113–116; (b) Omura,
S.; Matsuzaki, K.; Fujimoto, T.; Kosuge, K.; Furuya, T.; Fujita, S.; Nakagawa, A.
J. Antibiot. 1991, 44, 117–118.
15. Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651–1660.
16. Mono-ethyl fumarate (CAS 2459-05-4) is commercially available, and was
purchased from Fluka.
17. Crystallographic data (excluding structure factors) for compounds 16, 17 and 20
have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC 676079, 676078 and 676080 respectively.
Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK, (fax: þ44 (0) 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk).
18. We have observed similar lactonizations in related reactions: see Ref. 5d, and:
Lumby, R. J. R.; Joensuu, P. M.; Lam, H. W. Org. Lett. 2007, 9, 4367–4370.
19. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156; (b) Dess, D. B.;
Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
20. Miyake, H.; Yamamura, K. Chem. Lett. 1992, 507–508.