Stereoselective synthesis of a lactam analogue of brefeldin C

Article abstract of DOI:10.1055/s-2008-1042899

A convergent, stereoselective synthesis of a brefeldin C lactam analogue is described. Novel features are application of the asymmetric iridium-catalyzed allylic substitution on a multigram scale for construction of the stereogenic centers C-9 as well as C-15 and an intermolecular Nozaki-Hiyama-Kishi reaction for introduction of the brefeldin enoate moiety. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042899

LETTER
831
Stereoselective Synthesis of a Lactam Analogue of Brefeldin C
L
acta
m
Analoe
beldin C astian Förster, Günter Helmchen*
Organisch-Chemisches Institut, Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Fax +49(6221)544205; E-mail: g.helmchen@oci.uni-heidelberg.de
Received 30 December 2007
of the D10 double bond and conformational rigidity are es-
sential features. (d) Opening of the 13-membered lactone
leads to complete loss of biological activity.
Abstract: A convergent, stereoselective synthesis of a brefeldin C
lactam analogue is described. Novel features are application of the
asymmetric iridium-catalyzed allylic substitution on a multigram
scale for construction of the stereogenic centers C-9 as well as C-15
and an intermolecular Nozaki–Hiyama–Kishi reaction for introduc-
tion of the brefeldin enoate moiety.
Considering that lactone hydrolysis is a possible way of
deactivation in vivo, it was decided to synthesize a lactam
analogue of a brefeldin. A lactone–lactam shift has been
used successfully by Borzilleri et al.7 in the epothilone ar-
ea. While our work was almost completed, a synthesis of
the 4-epi-BFA lactam analogue was reported.8
Key words: brefeldin C, iridium-catalyzed allylic substitution,
ring-closing metathesis, Nozaki–Hiyama–Kishi reaction, Julia–Ko-
cieński olefination
Herein we want to present a synthesis of the BFC lactam
analogue 1. BFC is a direct precursor in the biosynthesis
of BFA,9 and BFC also shows biologic activity.10 Accord-
ingly, lactam 1 was a logical first target to test the effect
of the lactone–lactam shift on biological properties. Many
total syntheses of BFA11 and a few of BFC12 have been re-
ported; however, they were almost exclusively directed at
the known natural products. An exception is our own pre-
vious synthesis of BFA analogues.13
Brefeldin A (BFA) (Figure 1) was isolated as a metabolite
of penicillium decumbens in 19581 and shows significant
biological activity. Thus, BFA is used as an important tool
in cell biology in order to influence protein traffic in cell
organelles.2 In particular, its anticancer activity turned
BFA into an interesting target for medicinal chemistry.3
Problems associated with medicinal applications of BFA
as an anticancer agent are its poor solubility and poor
pharmacokinetics.4
Our planning was aimed at a strategy (Scheme 1), which
could be used for the stereoselective synthesis of a library
of brefeldin analogues of type A with a broad range of
functional groups, in particular in the five-membered ring
and in the lower side chain in positions 12–15.
OH
H
1
X
15
4
brefeldin A X = O, R = OH
brefeldin C X = O, R = H
1a X = NH, R = H
5
9
O
7
R
In this strategy the construction of the five-membered car-
bocycle B is based on the recently established combina-
tion of the iridium-catalyzed allylic alkylation and ring-
H
Figure 1 Brefeldins A and C: lactam analogue
Our aim was the synthesis of brefeldin analogues with im-
proved solubility3c and stability. Hori et al.5,6 have studied
the ability of BFA and several analogues to induce cell
differentiation in the human colonic carcinoma cell line
HCT 116. In addition, cytotoxicity was determined by a
MTT assay. The structure–activity studies have furnished
the following results: (a) The C1–C4 moiety with the 4R
configuration is essential; induction of apoptosis could be
detected at a minimum concentration of 0.11 mM for BFA,
but 70 mM for 4-epi-BFA. Furthermore, the cytotoxicity
of 4-epi-BFA is 300 times lower than that of BFA; in con-
trast, 4-O-acetyl-BFA exhibits even higher cytotoxicity
than BFA (IC50 values: 0.1 mM for 4-O-acetyl-BFA, 0.2
mM for BFA). Inducibility of apoptosis of 4-O-acetyl-
BFA is 2.5 times lower than that of BFA. (b) The influ-
ence of the C-7 moiety is less important, i.e. 7-O-acetyl-
BFA shows activity comparable to BFA. (c) The presence
SYNLETT 2008, No. 6, pp 0831–0836
x
x.
x
x.
2
0
0
8
Advanced online publication: 11.03.2008
DOI: 10.1055/s-2008-1042899; Art ID: G37907ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Retrosynthetic analysis for brefeldin lactam analogues

832
S. Förster, G. Helmchen
LETTER
closing metathesis (RCM).14 Functionalization of the dou-
ble bond of C can lead to at least three brefeldin lactam
analogues: (i) hydrogenation would lead to the BFC ana-
logue (FG1 = FG2 = H), (ii) oxymercuration would lead to
the BFA analogue (FG1 = OH, FG2 = H), and (iii) dihy-
droxylation would lead to the 6-hydroxy-BFA analogue
(FG1 = OH, FG2 = OH). Introduction of the lower side
chain was planned via Julia–Kocieński olefination, which
proceeded with high E selectivity in BFA syntheses car-
ried out by Trost et al.11 and by our group.13 For the upper
side chain, the Nozaki–Hiyama–Kishi reaction (NHK)
was considered, which has previously been used by
Schreiber et al.12 as an intramolecular version. Finally,
formation of the macrocycle by standard macrolactamiza-
tion was planned.
NC
CO2Me
OCPh3
OCPh3
1. [Ir(cod)Cl]2,
L*, TBD, THF
3
2.
MeO2C
CN
OCO2Me
CO2Me
OCPh3
2
NC
4
S
S
Ar
Ar
O
L1 Ar = Ph
L2 Ar = o-(MeO)C6H4
P
N
aS
O
Scheme 2 Iridium-catalyzed allylic alkylation (TBD = 1,5,7-tri-
azabicyclo[4.4.0]dec-5-ene)
The stereoselective synthesis of the five-membered-ring
synthon 6 began with an iridium-catalyzed allylic alkyla-
tion of the trityl-protected allylic carbonate 2 with methyl
cyanoacetate as pronucleophile (Scheme 2). The iridium
catalyst was prepared from [Ir(cod)Cl]2 and ligands L1 or
L2 by C–H activation with the strong base, 1,5,7-triaza-
bicyclo[4.4.0]dec-5-ene (TBD).15 At the beginning of this
work a scale of 0.5–1 mmol was typical for iridium-cata-
lyzed allylic substitutions. Considering that more than ten
steps were required for the synthesis of 1, scale-up was a
necessity. Another problem was the very low solubility of
the pronucleophile methyl sodium cyanoacetate in THF.
Both problems were solved with the help of salt-free con-
ditions,16 i.e. use of the conjugate acid of the nucleophile,
Table 1 Iridium-Catalyzed Allylic Alkylation of Carbonate 2 with
Methyl Cyanoacetate According to Scheme 2
Entry 2
(mmol)
L*
Ir cat.a Temp Time Yield of Ratio ee
(mol%) (°C) (h)
3 (%)b 3:4c (%)d
1
2
3
4
1
1
L1
L2
L1
L1
2
4
4
2
40
r.t.
r.t.
40
46
5
64
80
70
70
82:18 95
85:15 97
5
28
60
84:16 98
87:13 97
40
a For preparation of the catalyst see the general procedure.15
b Isolated yield.
which allowed reactions to be run with 2 mol% of the iri- c Determined by GC of the crude products.
d Determined by HPLC on a Daicel column after demethoxycarbony-
dium catalyst on a 40-mmol scale of carbonate 2 (Table 1,
entry 4).17 The branched product 3 was obtained in good
yield and high enantioselectivity (97% ee), after purifica-
tion by column chromatography, as a mixture of C2-
epimers.
lation.20
OCPh3
CN
OCPh3
CN
OCPh3
CHO
H
H
H
H
a–c
d, e
The branched substitution product 3 was alkylated with
allyl bromide, and the resulting diene was subjected to
RCM with 2 mol% of Grubbs’ I catalyst (Scheme 3). The
cyclization product was saponified, and the carboxylic
acid was subjected to thermal decarboxylation. Heating of
the acid had to be stopped after one hour in order to avoid
the loss of the trityl protecting group. Nitrile 5 was ob-
tained as a mixture of diastereoisomers.18 This was hydro-
genated using H2/Pd/C, and the product was treated with
DIBAL-H to give the aldehyde 6 as mixture of epimers in
excellent overall yield. Epimerization by reaction with a
catalytic amount of DBU furnished the trans diastereoiso-
mer with excellent diastereoselectivity (dr = 95:5).19
MeO2C
3
5
6
Scheme 3 Reagents and conditions: (a) NaH (1.3 equiv), C3H5Br
(1.4 equiv), THF, r.t., 24 h, 88%; (b) Grubbs’ I catalyst (2 mol%),
CH2Cl2, reflux, 8 h, 79%; (c) LiOH, THF–H2O (1:1), r.t., 1 h, then
DMF, 150 °C, 1 h, 73%; (d) Pd/C, H2, MeOH, r.t., 1 h, 89%; (e) DI-
BAL-H (2.2 equiv), CH2Cl2, –78 °C, then 20% DBU, CH2Cl2, r.t.,
88% (6, dr 95:5).
tion using an ylid derived from the phosphonium bromide
[PPh3(CH2)3OBn]Br (13), which was prepared as previ-
ously described.23 The resulting olefin was subjected to
catalytic hydrogenation to give the alcohol 11, which was
transformed into the tetrazolylsulfone 12 using a standard
protocol.24 The ee value of this compound was only 79%,
because of partial racemization during the Wittig olefina-
tion. Fortunately, a single recrystallization gave the com-
pound with 98% ee.
The tetrazolylsulfone 12 (Scheme 4) was prepared via the
aminoaldehyde 10, which was either derived from L-ala-
nine or prepared by iridium-catalyzed allylic amination21
followed by ozonization. Thus, trans-crotyl methyl car-
bonate (7) was aminated highly enantio- and regioselec-
tively with the ammonia equivalent 8, which has been
developed by our group.22 Selective deprotection by re-
moval of the formyl group under basic conditions and
subsequent ozonolysis yielded the Boc-protected ami-
noaldehyde 10, which was subjected to a Wittig olefina-
The chiral building blocks 6 and 12 were combined with
a Julia–Kocieński olefination, which produced the olefin
14 with high E selectivity (>10:1) and excellent yield
(Scheme 5).25 Treatment of 14 with AcOH–H2O (4:1) ef-
Synlett 2008, No. 6, 831–836 © Thieme Stuttgart · New York

LETTER
Lactam Analogue of Brefeldin C
833
OCPh3
Boc
CHO
H
H
N
CHO
H
CHO
Boc
8
NHBoc
1
a
b,c
NHBoc
2'
1'
NHBoc
N
5
6
5'
b
a
O
MeO2CO
3
3
H
H
14
15
7
9
10
H
c, d
CO2Me
d
17
I
N
R1
R2
N
NHBoc
NHBoc
H
e, f
N
1
N
( )3
( )3
4
S
HO
CO2Me
1'
2'
16a R1 = H, R2 = OH
16b R1 = OH, R2 = H
NHBoc
O
O
Ph
12
11
6''
1''
H
Scheme 4 Reagents and conditions: (a) [Ir(cod)Cl]2 (1 mol%), L2
(2 mol%), THF, r.t., 1.5 h, >96% ee, branched/linear = 99:1, 85%; (b)
KOH, MeOH, 86%; O3, CH2Cl2–MeOH, –78 °C, 10 min, PPh3, 60%;
(c) KHMDS (1.05 equiv), [PPh3(CH2)3OBn]Br (13; 1.05 equiv), 0 °C,
THF, 2.5 h, 66%, 79% ee; (d) Pd(OH)2/C (0.6 mol%), MeOH, 5 h, r.t.,
74%; (e) PPh3 (1.14 equiv), DEAD (1.04 equiv), 1-phenyltetrazolyl-
5-thiol (1.04 equiv), THF, 0 °C → r.t., 4 h, 87%; (f) H2O2 (10 equiv),
(NH4)6Mo7O24 (0.2 equiv), EtOH, r.t., 4 h, 98% ee after one recrystal-
lization, 50%.
e
R1
R2
H
H
18a R1 = H, R2 = OH
18b R1 = OH, R2 = H
COOH
NH2
f
R1
H
R2
19a R1 = H, R2 = OAc
H
fected selective cleavage of the trityl group to give the
corresponding alcohol, which was oxidized to the alde-
hyde 15 using the Swern method.
N
h
g
O
1a R1 = H, R2 = OH
1b R1 = OH, R2 = H
H
The NHK reaction with 15 and methyl (E)-3-iodoacrylate
(17)26 under standard conditions proceeded with compar-
atively high diastereoselectivity (16a:16b = 1:5).27,28 It
was not possible to separate the diastereoisomers. The
configuration of the stereogenic center C-4 was deter-
mined via preparation of the (S)- and (R)-(2-phenyl)propi-
onates of 16a,b and their analysis by 1H NMR.29 It turned
out that the undesired 16b was the major product.
Scheme 5 Reagents and conditions: (a) 12, KHMDS, DME, –78
°C, 83%; (b) AcOH–H2O (4:1), 1 h, 50 °C, 78%; (c) (COCl)2, DMSO,
Et3N, CH2Cl2, –78 °C, 96%; (d) CrCl2 (4 equiv), 1% NiCl2, 17 (2
equiv), THF, r.t., dr = 5:1, 72%; (e) LiOH, THF–H2O, r.t., 24 h, then
CF3CO2H, 1 h, 80%; (f) EDCI, N-hydroxybenzotriazole (HOBt),
DMF, r.t., 24 h, c = 0.025 M, 84%, chromatographic separation of 1a
and 1b; (g) MsCl, DMAP, Et3N, pyridine, 0 °C, 1.5 h, aq workup, then
CsOAc, DMF, 80 °C, 16 h, 32% of 19a and 18% of 1a; (h) LiOH (8
equiv), MeOH–H2O (2:1), 40 °C, 5.5 h, 79%.
The 1:5 mixture of 16a and 16b was deprotected by treat-
ment with LiOH and then trifluoroacetic acid to give the
amino acid 18,30 which without purification was subjected
to macrolactamization using conditions reported by Borz-
illeri et al.7 for their syntheses of epothilone lactam ana-
logues. The resultant epimers 1a and 1b, formed as a 1:5
mixture, were separated by flash chromatography. The
yield of 1 from carbonate 2 was 8.4% over 12 steps and
4.4% for 1a over 14 steps.
18% of 1a.32,33 The acetate 19a was saponified to give
1a.34
In conclusion, we have developed a convergent, stereose-
lective synthesis of a brefeldin C lactam analogue. Impor-
tant elements of this synthesis are iridium-catalyzed
allylic substitutions on a multigram scale for construction
of the stereogenic centers C-9 as well as C-15 and the use
of an intermolecular Nozaki–Hiyama–Kishi reaction for
introduction of the enoate moiety. Current work in our
group is directed at the synthesis of further brefeldin ana-
logues.
4-epi-BFA has been reported to be biologically almost in-
active.6 Therefore, it was important to invert the stereo-
genic center C-4 of 1b. We probed an oxidation–reduction
sequence as well as inversion via nucleophilic displace-
ment.
Acknowledgment
Oxidation/reduction seemed straightforward, because it
has been reported that reduction of 7-O-MEM- and 7-O-
This work was supported by the Deutsche Forschungsgemeinschaft
MOM-4-dehydro-BFA with NaBH4 (methanol, –78 °C) (GK 850). We thank Olena Tverskoy and Daniel Weickmann for
motivated and competent experimental assistance and Prof. Klaus
yields the BFA derivatives with high diastereoselectivi-
ty.31 Accordingly, lactam 1b was oxidized with 2-iodoxy-
Ditrich (BASF AG) for enantiomerically pure 1-arylethylamines.
benzoic acid (IBX) in DMSO, and the resultant ketone
was reduced with NaBH4. To our surprise, 1b was formed
with high diastereoselectivity (1b:1a 10:1, GC–MS).
The same observation was made by Suh et al. in their syn-
thesis of the 4-epi-BFA lactam analogue.8 Next, alcohol
1b was transformed into the O-mesyl derivative, and this
was reacted with CsOAc in DMF to yield 32% of 19a and
References and Notes
(1) Singleton, V. L.; Bohonos, N.; Ullstrup, A. J. Nature
(London) 1958, 181, 1072.
(2) Sciaky, N.; Presley, J.; Smith, C.; Zaal, K. J. M.; Cole, N.;
Moreira, J. E.; Terasaki, M.; Siggia, E.; Lippincott-
Synlett 2008, No. 6, 831–836 © Thieme Stuttgart · New York

834
S. Förster, G. Helmchen
LETTER
Schwartz, J. J. Cell Biol. 1997, 139, 1137; and literature
cited therein.
(3) (a) Betina, V.; Horakova, K.; Barath, Z.
H, ArH), 7.38–7.45 (m, 6 H, ArH). 13C NMR (75.48 MHz,
CDCl3): d = 39.82 (d, CHCN), 44.98 (d, CHCH2), 53.43 (q,
CO2CH3), 63.72 (t, CH2O), 87.42 (s, CPh3), 114.76 (s, CN),
120.69 (t, CH=CH2), 127.42, 128.12, 128.68 (3 × d, CAr),
132.27 (d, CH=CH2), 143.67 (s, CAr), 166.32 (s, CO2Me).
MS (EI+): m/z (%) = 411 (3) [M+], 334 (4) [M – Ph+], 259 (9),
Naturwissenschaften 1962, 51, 445. (b) Argade, A. B.;
Devraj, R.; Vroman, J. A.; Haugwitz, R. D.; Hollingshead,
M.; Cushman, M. J. Med. Chem. 1998, 41, 3337. (c) Fox,
B. M.; Vroman, J. A.; Fanwick, P. E.; Cushman, M. J. Med.
Chem. 2001, 44, 3915. (d) Anadu, N. O.; Davisson, V. J.;
Cushman, M. J. Med. Chem. 2006, 49, 3897.
+
+
244 (37) [HCPh3 ], 243 (100) [CPh3 ], 165 (66), 152 (42)
[M – OCPh3 ], 105 (32) [PhCO+], 77 (16) [Ph+]. Anal. Calcd
+
for C27H25NO3: C, 78.81; H, 6.12; N, 3.40. Found: C, 78.83;
H, 6.32; N, 3.28.
(4) Phillips, L. R.; Supko, J. G.; Malspeis, L. Anal. Biochem.
1993, 211, 16.
(5) Zhu, J.-W.; Hori, H.; Nojiri, H.; Tsukuda, T.; Taira, Z.
Bioorg. Med. Chem. Lett. 1997, 139.
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Y.; Ohkura, K.; Hori, H. Bioorg. Med. Chem. 2000, 8, 455.
(7) Borzilleri, R. M.; Zheng, X.; Schmidt, R. J.; Johnson, J. A.;
Kim, S.-H.; DiMarco, J. D.; Fairchild, C. R.; Gougoutas, J.
Z.; Lee, F. Y. F.; Long, B. H.; Vite, G. D. J. Am. Chem. Soc.
2000, 122, 8890.
(8) Paek, S.-M. P.; Seo, S.-Y.; Min, K.-H.; Shin, D. M.; Chung,
Y. K.; Suh, Y.-G. Heterocycles 2007, 71, 1059.
(9) Sunagawa, M.; Ohta, T.; Nozoe, S. J. Antibiotics 1983, 25.
(10) Zeeh, J.-C.; Zeghouf, M.; Grauffel, C.; Guibert, B.; Martin,
E.; Dejaegere, A.; Cherfils, J. J. Biol. Chem. 2006, 281,
11805.
(11) Trost, B. M.; Crawley, M. L. Chem. Eur. J. 2004, 10, 2237;
this article contains an extensive bibliography of previous
total syntheses of Brefeldin A.
(12) (a) Latest total synthesis: Archambaud, S.; Aphecetche-
Julienne, K.; Guingant, A. Synlett 2005, 139. (b) First total
synthesis: Schreiber, S. L.; Meyers, H. V. J. Am. Chem. Soc.
1988, 110, 5198.
(18) The isomers (cis-5/trans-5 = 59:41) could be separated by
column chromatography on silica gel. Their relative
configuration was determined by 1D NOE–1H NMR
spectroscopy. HPLC data for cis-5: Daicel Chiralcel AD-H
(250 × 4.6 mm, 5 mm), with guard cartridge (10 × 4 mm, 5
mm), n-hexane–i-PrOH (99:1), flow rate = 0.5 mL min–1, r.t.,
UV detection at l = 210 nm, tR[(+)-(1R,2S)-5] = 25 min,
tR[(–)-(1S, 2R)-5] = 32 min.
(19) Analytical Data for (1R,2R)-2-[(Trityloxy)methyl]cyclo-
pentanecarbaldehyde (6): [a]D20 –8.9 (c = 0.525, CHCl3).
1H NMR (300.13 MHz, CDCl3): d = 1.24–1.38 (m, 1 H, 3-
H), 1.50–1.62 (m, 2 H, 4-H), 1.63–1.91 (m, 3 H, 3-H, 5-H),
2.39–2.58 (m, 2 H, 1-H, 2-H), 2.97 (dd, J = 8.2, 8.2 Hz, 1 H,
CH2O), 3.19 (dd, J = 5.5, 8.9 Hz, 1 H, CH2O), 7.17–7.45 (m,
15 H, ArH), 9.70 (d, J = 2.3 Hz, 1 H, CHO). 13C NMR (75.48
MHz, CDCl3): d = 25.09 (t, C-4), 26.78 (t, C-5), 29.68 (t, C-
3), 41.78 (d, C-2), 55.85 (d, C-1), 66.58 (t, CH2OCPh3),
86,81 (s, CPh3), 127.07, 127.90, 128.81 (3 × d, CAr), 144.24
(s, CAr), 203.86 (s, CHO). HRMS (FAB+): m/z [M + Na+]
calcd for C26H26O2Na: 393.1831; found: 393.1839.
(20) HPLC Data for (3S)-3-[(Trityloxy)methyl]pent-4-
enenitrile (3¢) (Table 1): Daicel Chiralcel AD-H (250 × 4.6
mm, 5 mm) with guard cartridge (10 × 4 mm, 5 mm), n-
hexane–i-PrOH (99:1), flow rate = 0.5 mL min–1, r.t., l =
210 nm, tR[(–)-(R)-3¢] = 18 min, tR[(+)-(S)-3¢] = 20 min.
(21) tert-Butyl Formyl(1-methylprop-2-en-1-yl)carbamate
[(–)-(S)-9]: A solution of the catalyst in anhyd THF (1 mL)
was prepared according to the general procedure from
[Ir(cod)Cl]2 (13.4 mg, 0.01 mmol), (R,R,R)-L2 (24.0 mg,
0.02 mmol) and TBD (11.1 mg, 0.40 mmol). Carbonate 7
(265 mg, 2.0 mmol) and Boc(CHO)NH (8; 477 mg, 2.2
mmol) were added, and the solution was stirred for 1.5 h at
r.t. The solvent was removed under reduced pressure, and
the ratio of branched and linear product was determined by
1H NMR. Flash column chromatography on silica gel (PE–
EtOAc, 20:1) afforded pure (–)-(S)-9 (85%) as a colorless
oil; [a]D20 –36.9 [c = 1.08, CHCl3, 96% ee determined by
chiral Chrompack permethyl-b-cyclodextrin (25 m × 0.25
mm), temperature program: gradient 4 °C/min: 50–90 °C,
injector temperature 200 °C], tR[(–)-(S)-9] = 37.8 min, tR
[(+)-(R)-9] = 38.9 min. 1H NMR (300.13 MHz, CDCl3): d =
1.41 (d, J = 6.9 Hz, 3 H, CHMe), 1.53 (s, 9 H, t-Bu), 5.01–
5.19 (m, 3 H, CHN, CH=CH2), 6.00 (ddd, J = 5.9, 10.3, 17.2
Hz, 1 H, CH=CH2), 9.17 (s, 1 H, CHO). 13C NMR (75.48
MHz, CDCl3): d = 17.92 (q, CHMe), 28.21 (q, t-Bu), 49.40
(d, CHNH), 84.17 (s, t-Bu), 115.78 (t, CH=CH2), 138.10 (d,
CH=CH2), 152.51 (s, CO2t-Bu), 163.25 (d, CHO). MS (EI+):
(13) Hübscher, T.; Helmchen, G. Synlett 2006, 1323.
(14) Streiff, S.; Welter, C.; Schelwies, M.; Lipowsky, G.; Miller,
N.; Helmchen, G. Chem. Commun. 2005, 2957.
(15) General Procedure for the Preparation of the Iridium
Catalyst: Under argon, a mixture of [Ir(cod)Cl]2 (0.02
mmol), L* (0.04 mmol) and anhyd 1,5,7-triaza-
bicyclo[4.4.0]dec-5-ene (TBD, 0.08 mmol) was dissolved in
anhyd THF (1.0 mL, content of H2O <30 mg/L, Karl Fischer
titration) and the solution was stirred for 5 min (L2) or 1.5 h
(L1). TBD is hygroscopic and was dried under vacuum in a
Schlenk tube and stored under argon. For preparation of the
ligands see: (a) L1:van Zijl, A. W.; Arnold, L. A.; Minnaard,
A. J.; Feringa, B. L. Adv. Synth. Catal. 2004, 326, 413;
supporting information. (b) L2: Polet, D.; Alexakis, A. Org.
Lett. 2005, 7, 1621; supporting information.
(16) Gnamm, C.; Förster, S.; Miller, N.; Brödner, K.; Helmchen,
G. Synlett 2007, 790.
(17) Methyl(3R)-2-Cyano-3-[(trityloxy)methyl]pent-4-enoate
(3): A solution of the catalyst in anhyd THF (20 mL) was
prepared according to the general procedure from
[Ir(cod)Cl]2 (268 mg, 0.40 mmol), L1 (432 mg, 0.80 mmol)
and TBD (222 mg, 1.60 mmol). Carbonate 2 (15.54 g, 40.0
mmol), the pronucleophile (5.11 g, 51.6 mmol) and anhyd
THF (60 mL) were added, and the solution was stirred at 40
°C. Conversion as well as the ratio of branched and linear
product were determined by GC. After 60 h the solvent was
removed under reduced pressure, and the residue was
subjected to flash column chromatography on silica gel (PE–
EtOAc, 20:1) to yield 3 (70%) as a pale yellow oil which was
an inseparable mixture of epimers. Their ratio was
determined by 1H NMR (64:36). 1H NMR (300.13 MHz,
CDCl3, major epimer): d = 2.90–3.09 (m, 1 H, CHCH2),
3.17–3.40 (m, 2 H, CH2O), 3.75 (s, 3 H, OMe), 4.14 (d, J =
4.3 Hz, 1 H, CHCN), 5.09–5.21 (m, 2 H, CH=CH2), 5.63
(ddd, J = 8.8, 10.4, 17.0 Hz, 1 H, CH=CH2), 7.20–7.35 (m, 9
+
+
m/z (%) = 143 (18) [M – C4H8 ], 57 (100) [C4H7 ]. Anal.
Calcd for C10H17NO3: C, 60.28; H, 8.60; N, 7.03. Found: C,
60.00; H, 8.54; N, 7.13.
This preparation was also carried out on a 77-mmol scale
with 1 mol% of L1 as ligand to give 9 with 94% ee,
branched/linear = 98:2. Amide 10 was obtained after
saponification in 81% yield over two steps.
(22) Weihofen, R.; Tverskoy, O.; Helmchen, G. Angew. Chem.
Int. Ed. 2006, 45, 5546; Angew. Chem. 2006, 118, 5673.
Synlett 2008, No. 6, 831–836 © Thieme Stuttgart · New York

LETTER
Lactam Analogue of Brefeldin C
835
(23) We used a simplified version of a method described in:
Ziegler, F. E.; Klein, S. I.; Pati, U. K.; Wang, T. F. J. Am.
Chem. Soc. 1985, 107, 2730.
Bu), 167.19 (s, CO2Me). MS (HR–EI+): m/z [M+] calcd for
C22H37O5N: 395.2689; found: 395.2672. MS: m/z [M – CO2
– C4H8 ] calcd for C17H29O3N: 295.2147; found: 295.2106.
+
(24) Blakemore, P. R.; Kocieński, P. J.; Marczak, S.; Wicha, J.
(28) In principle, the side chains can be introduced in reversed
order, because of a hidden symmetry of 6. However, the
NHK reaction with aldehyde 6 proceeded with poor
diastereoselectivity of 2:1. Various experiments to effect a
reagent-controlled reaction using Kishi’s method failed:
Namba, K.; Kishi, Y. Org. Lett. 2004, 6, 5031.
Synthesis 1999, 1209.
(25) Preparation of 14: A solution of KHMDS in toluene (0.5
M, 5.6 mL) was added dropwise to a cooled solution (–78
°C) of 12 (1.188 g, 2.907 mmol) in DME (11 mL, freshly
dried over sodium, containing 70 mg H2O/mL DME, Karl
Fischer titration). After 35 min a solution of 6 (821 mg,
2.216 mmol) in DME (11 mL) was added dropwise. After 3
h at –78 °C the solution was allowed to warm to r.t. and was
stirred for 60 min. Then H2O (10 mL) and brine (10 mL)
were added and the mixture was extracted with Et2O (3 × 20
mL). The combined organic layers were dried over Na2SO4,
filtered, and the solvent was evaporated in vacuo. The
residue was subjected to flash column chromatography on
silica gel (PE–EtOAc, 10:1) to give 14 (1.030 g, 83%) as a
colorless oil; [a]D20 –19.5 (c = 1.33, CHCl3). 1H NMR
(500.13 MHz, CDCl3): d = 1.06 (d, J = 6.6 Hz, 3 H, CHMe),
1.20–1.40 (m, 5 H, 3-H2, 2-H2, 5¢-H), 1.40–1.68 (m, 3 H, 3¢-
H, 4¢-H2), 1.44 (s, 9 H, t-Bu), 1.71–1.83 (m, 2 H, 2¢-H, 5¢-H),
1.83–1.95 (m, 3 H, 4-H2, 3¢-H), 2.14 (mc, 1 H, 1¢-H), 2.92
(dd, J = 6.5, 8.8 Hz, 1 H, CH2O), 3.10 (dd, J = 4.9, 8.8 Hz, 1
H, CH2O), 3.59 (br s, 1 H, 1-H), 4.26 (br s, 1 H, NH), 5.21
(ddd, J = 6.3, 6.3, 15.3 Hz, 1 H, 5-H), 5.28 (dd, J = 7.6, 15.3
Hz, 1 H, 6-H), 7.19–7.47 (m, 15 H, H-Ar). 13C NMR (125.76
MHz, CDCl3): d = 21.42 (q, CHMe), 24.26 (t, C-4¢), 26.12
(t, C-3), 28.61 (q, t-Bu), 29.82 (t, C-3¢), 32.55 (t, C-4), 33.63
(t, C-5¢), 36.92 (t, C-2), 46.25 (d, C-1¢), 46.58 (d, C-1), 46.58
(d, C-2¢), 65.79 (t, CH2O), 79.06 (s, t-Bu), 86.27 (s, CPh3),
126.89, 127.75, (2 × d, C-Ar), 128.96 (d, C-Ar), 129.10 (d,
C-5), 134.80 (d, C-6), 144.69 (s, CAr), 155.51 (s, CO2t-Bu).
Anal. Calcd for C37H47NO3: C, 80.25; H, 8.55; N, 2.53.
Found: C, 80.00; H, 8.46; N, 2.57. MS (FAB+): m/z = 576.3
[M + Na+].
(29) Helmchen, G. Tetrahedron Lett. 1974, 1527.
(30) Preparation of (–)-1b: A solution of 16 (338 mg, 0.86
mmol) in THF (7 mL) was treated with an aqueous solution
of LiOH (1 M, 7 mL). After stirring for 24 h at r.t. HCl (1 M,
10 mL) and EtOAc (10 mL) were added. The aqueous layer
was separated and extracted with EtOAc (3 × 10 mL). The
combined organic layers were dried over NaSO4, filtered and
the solvent was removed in vacuo. The residue was
dissolved in CH2Cl2 (9 mL) and TFA (2 mL) was added.
After stirring for 1 h at r.t. the volatile components were
removed in vacuo. A solution of the residue in MeOH–H2O
(10:1) was filtered through a column of the strongly acidic
ion-exchange resin Dowex 50 W X 8 (10 g). The column
was eluted with a solution of NH3 (0.2–2 M) in MeOH–H2O
(10:1) to yield 18 as a white microcrystalline powder (194
mg, 80%).
Under argon EDCI (310 mg, 1.62 mmol) and HOBt (122 mg,
0.91 mmol) were added to a cooled (0 °C) suspension of 18
(182 mg, 0.65 mmol) in DMF (26 mL). After 20 min the
mixture was allowed to warm to r.t. The mixture became a
clear solution after 10 min that was stirred for further 24 h.
Then brine (20 mL) and EtOAc (20 mL) were added. The
aqueous layer was separated and extracted with EtOAc (4 ×
20 mL). The combined organic layers were washed with an
aqueous solution of NaOH (1 M, 10 mL), dried over Na2SO4,
filtered, and the solvent was evaporated in vacuo. The
residue was subjected to flash chromatography on silica gel
(EtOAc) to yield a mixture of 1a and 1b (143 mg, 84%) as
small needles. The components were separated by flash
chromatography using PE–EtOAc (1:5) as eluent.
(26) The ester 17 was prepared by cis-selective addition of HI to
propargylic acid and esterification, cf.: Dixon, J. D.; Ley, S.
V.; Longbottom, A. D. Org. Synth. 2003, 80, 129.
(27) Preparation of 16: Under an atmosphere of argon, CrCl2
(573 mg, 4.68 mmol) was added to a mixture of 15 (362 mg,
1.17 mmol), methyl (2E)-3-iodoacrylate (17; 495 mg, 2.34
mmol) and NiCl2 (2.6 mg, 0.012 mmol) in anhyd THF (5
mL) at r.t. After stirring the brownish suspension for 1 h
TLC monitoring showed complete conversion. The mixture
was treated with H2O and filtered through a pad of silica gel,
which was washed with Et2O. The solvent was evaporated in
vacuo and the residue was subjected to flash
Analytical data of the major epimer 1b: [a]D20 –18.5 (c =
0.40, MeOH). 1H NMR (300.13 MHz, CD3OD): d = 1.00–
1.40 (m, 3 H, 7-H or 13-H, 14-H2), 1.14 (d, J = 6.8 Hz, 3 H,
Me), 1.40–1.68 (m, 2 H, 7-H or 13-H), 1.68–2.10 (m, 9 H, 5-
H, 6-H2, 12-H2, 8-H2, 7-H or 13-H, OH), 2.57 (mc, 1 H, 9-H),
3.85–4.03 (m, 1 H, 15-H), 4.45 (br s, 1 H, 4-H), 5.14 (dd,
J = 3.7, 14.9 Hz, 1 H, 10-H), 5.52 (ddd, J = 3.9, 10.7, 14.7
Hz, 1 H, 11-H), 6.08 (dd, J = 1.3, 15.8 Hz, 1 H, 2-H), 6.48
(dd, J = 4.1, 15.8 Hz, 1 H, 3-H). 13C NMR (75.48 MHz,
CD3OD): d = 21.16 (q, Me), 27.16 (t, C-7 or C-13), 27.21 (t,
C-7 or C-13), 31.43 (t, C-6), 34.41 (t, C-12), 37.34 (t, C-8),
38.01 (t, C-14), 43.39 (d, C-9), 47.64 (d, C-15), 50.67 (d, C-
5), 72.61 (d, C-4), 123.53 (d, C-2), 130.96 (d, C-11), 138.46
(d, C-10), 147.59 (d, C-3), 170.85 (s, CONH). MS (HR–
EI+): m/z [M+] calcd for C16H25O2N: 263.1886; found:
263.1868. MS: m/z [M – H2O+] calcd for C16H23ON:
245.1780; found: 245.1788.
chromatography on silica gel (PE–EtOAc, 9:1) to yield 16
(338 mg, 72%) as a colorless oil.
NMR data of the major diastereoisomer 16b: 1H NMR
(500.13 MHz, CDCl3): d = 1.10 (d, J = 6.6 Hz, 3 H, CHMe),
1.30–1.48 (m, 6 H, 5¢¢-H2, 4¢¢-H2, 5¢-H, 3¢-H), 1.43 (s, 9 H, t-
Bu), 1.48–1.70 (m, 2 H, 4¢-H), 1.71–1.86 (m, 3 H, 1¢-H, 5¢-
H, 3¢-H), 1.94–2.06 (m, 2 H, 3¢¢-H), 2.25–2.35 (m, 1 H, 2¢-
H), 2.40 (br s, 1 H, OH), 3.56–3.67 (m, 1 H, CHNH), 3.74
(s, 3 H, OMe), 4.24 (mc, 1 H, CHOH), 4.34 (br s, 1 H, NH),
5.42 (dd, J = 8.5, 15.3 Hz, 1 H, CH=CHCH2), 5.50 (ddd, J =
6.4, 6.4, 15.2 Hz, 1 H, CH=CHCH2), 6.06 (dd, J = 1.7, 15.6
Hz, 1 H, CH=CHCO2Me), 6.94 (dd, J = 4.0, 15.6 Hz, 1 H,
CH=CHCO2Me). 13C NMR (125.76 MHz, CDCl3): d =
21.31 (q, CHMe), 24.15 (t, C-4¢), 25.84 (t, C-4¢¢), 28.37 (t,
C-5¢), 28.59 (q, t-Bu), 32.25 (t, C-3¢¢), 34.15 (t, C-3¢), 36.72
(t, C-5¢¢), 46.43 (d, CHNH), 48.04 (d, C-2¢), 51.69 (q, OMe),
51.74 (d, C-1¢), 75.42 (d, C-4), 79.16 (s, t-Bu), 120.42 (d,
CH=CHCO2Me), 130.72 (d, CH=CHCH2), 135.50 (d,
CH=CHCH2), 148.95 (d, CH=CHCO2Me), 155.54 (s, CO2t-
(31) (a) Corey, E. J.; Wollenberg, R. H. Tetrahedron Lett. 1976,
4705. (b) Bartlett, P. A.; Green, F. R. J. Am. Chem. Soc.
1978, 100, 4858.
(32) Preparation of (–)-19: Mesyl chloride (142 mL, 1.82 mmol)
was added dropwise to a solution of 1b (80 mg, 0.30 mmol),
Et3N (253 mL, 1.82 mmol) and DMAP (37 mg, 0.30 mmol)
in pyridine (10 mL) at 0 °C. The bright orange solution was
stirred for 0.5 h at this temperature. Then H2O (10 mL) was
added, and the mixture was allowed to warm to r.t. After
stirring for 10 min the solution was diluted with EtOAc (10
mL) and a sat. aq solution of CuSO4 (10 mL) was added. The
Synlett 2008, No. 6, 831–836 © Thieme Stuttgart · New York

836
S. Förster, G. Helmchen
LETTER
aqueous layer was separated and extracted with EtOAc (3 ×
10 mL). The combined organic layers were washed with a
sat. aq solution of NaHCO3 (20 mL), dried over Na2SO4,
filtered, and the solvent was removed under reduced
C-15), 48.62, (d, C-9), 50.80 (d, C-5), 79.81 (d, C-4), 125.93
(d, C-2), 131.75 (d, C-11), 137.16 (d, C-10), 142.00 (d, C-1),
169.71 (s, C-1), 172.04 (s, CO2Me). MS (HR–EI+): m/z [M+]
calcd for C18H27O3N: 305.1991; found: 305.1969. MS: m/z
+
pressure. A mixture of the residue with DMF (10 mL) and
CsOAc (350 mg, 1.82 mmol) was heated at 80 °C. After 19
h, brine and EtOAc were added. The aqueous layer was
separated and extracted with EtOAc (3 × 10 mL). The
combined organic layers were dried over Na2SO4 and
filtered. The solvents were removed under reduced pressure
and the residue was subjected to flash chromatography on
silica gel (PE–EtOAc, 1:5) to yield 19 (29.8 mg, 32%) as
colorless needles and 1a (14.3 mg, 18%): [a]D20 –64.9 (c =
0.32, MeOH). 1H NMR (300.13 MHz, CD3OD): d = 1.15 (d,
J = 6.8 Hz, 3 H, 16-H), 1.00–1.20 (m, 1 H, 13-H or 7-H),
1.20–1.50 (m, 3 H, 14-H, 8-H, 6-H), 1.50–1.70 (m, 2 H, 13-
H2 or 7-H2), 1.70–1.90 (m, 5 H, 8-H or 14-H, 12-H, 7-H or
13-H, 5-H), 1.90–2.10 (m, 2 H, 6-H, 12-H), 2.07 (s, 3 H,
MeCO), 2.19–2.32 (m, 1 H, 9-H), 3.85–4.00 (m, 1 H, 15-H),
5.05–5.23 (m, 2 H, 4-H, 10-H), 5.55–5.71 (m, 1 H, 11-H),
5.91 (d, J = 16.1 Hz, 1 H, 2-H), 6.43 (dd, J = 6.7, 16.1 Hz, 1
H, 3-H). 13C NMR (75.48 MHz, CD3OD): d = 20.88 (q,
CHMe or CO2Me), 21.15 (q, CHMe or CO2Me), 25.79 (t, C-
7 or C-13), 27.45 (t, C-7 or C-13), 32.12 (C-6), 33.97 (t, C-
12), 36.75 (t, C-14 or C-8), 37.72 (t, C-14 or C-8), 47.62 (d,
[M – C2H3O2 ] calcd for C16H24ON: 246.1858; found:
246.1867.
(33) A Mitsunobu reaction with 1b failed to give a useful result.
(34) Analytical Data for (–)-1a: [a]D20 –20.1 (c = 0.165, MeOH).
1H NMR (500.13 MHz, CD3OD): d = 0.97–1.08 (m, 1 H, 13-
H or 7-H), 1.15 (d, J = 6.8 Hz, 3 H, Me), 1.21–1.45 (m, 2 H,
8-H, 14-H), 1.45–1.71 (m, 4 H, 6-H, 13-H2 or 7-H2, 5-H),
1.71–1.86 (m, 5 H, 8-H, 12-H, 14-H, 13-H or 7-H, OH),
1.92–2.05 (m, 2 H, 6-H, 12-H), 2.20 (mc, 1 H, 9-H), 3.87–
3.96 (m, 2 H, 4-H, 15-H), 5.16 (dd, J = 9.6, 15.2 Hz, 1 H, 10-
H), 5.64 (ddd, J = 4.2, 10.7, 15.0 Hz, 1 H, 11-H), 5.91 (dd,
J = 1.1, 16.1 Hz, 1 H, 2-H), 6.63 (dd, J = 5.9, 16.1 Hz, 1 H,
3-H). 13C NMR (125.75 MHz, CD3OD): d = 21.26 (q, Me),
25.95 (t, C-7 or C-13), 27.70 (t, C-7 or C-13), 32.49 (t, C-6),
33.79 (t, C-12), 36.78 (t, C-8), 37.55 (t, C-14), 47.55 (d, C-
15), 48.69 (d, C-9), 53.76 (d, C-5), 77.80 (d, C-4), 123.58 (d,
C-1), 131.33 (d, C-11), 137.88 (d, C-10), 147.44 (d, C-3),
170.56 (s, C-1). MS (HR–EI+): m/z [M+] calcd for
C16H25O2N: 263.1886; found: 263.1904. MS: m/z [M –
H2O+] calcd for C16H23ON: 245.1780; found: 245.1785.
Synlett 2008, No. 6, 831–836 © Thieme Stuttgart · New York