A synthesis of the C3-C15

Article abstract of DOI:10.1055/s-0029-1218537

Ring-closing metathesis and an allylation-elimination reaction sequence have been used to complete a synthesis of the conjugated triene subunit of the archazolids. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218537

LETTER
107
A Synthesis of the C3–C15 Fragment of the Archazolids
S
C
r
–C Fra
e
gment of
tg
ods ry W. O’Neil,* Matthew J. Black
Department of Chemistry, Western Washington University, Bellingham, WA 98225, USA
Fax +1(360)6502826; E-mail: oneil@chem.wwu.edu
Received 8 July 2009
Negishi and Huang recently described an elegant solution
to this subunit exploiting a regio- and stereoselective hy-
droboration of haloalkynes.9 Our retrosynthetic analysis,
including macrocycle formation by ring-closing metathe-
sis (RCM) at C13–C14 and olefination at C2–C3, requires
the synthesis of a previously unknown Z,Z-terminal triene
(Scheme 1). We questioned if two recently reported meth-
ods for the stereoselective construction of terminal 1,3-
butadienes could be extended to substituted conjugated
Abstract: Ring-closing metathesis and an allylation–elimination
reaction sequence have been used to complete a synthesis of the
conjugated triene subunit of the archazolids.
Key words: stereoselective synthesis, tandem reactions, allyla-
tions, eliminations, metathesis
Archazolid A and B, along with the glucopyranoside de-
rivative archazolid C, represent a family of structurally re-
lated natural products isolated from the myxobacterium
Archangium gephyra (Figure 1).1 They display powerful
growth-inhibitory activity against a number of murine and
human cancer cell lines based on the selective inhibition
of vacuolar-type ATPase.2
triene
synthesis.
Specifically,
TMS-substituted
allylboration10 or allylziroconation11 followed by syn-
Peterson elimination12 would provide rapid access to this
motif.
9
RCM
allylation–
elimination
OH
OH
HO
O
14
15
O
TBS
MeO
R2
MeO
O
HO
R1
HWE
O
NH
O
N
Me
1
O
NH
O
O
N
Me
O
O
S
archazolid A
S
O
O
A (R1 = Me R2 = H)
M
R1
archazolid
TMS
B (R1 = H R2 = H)
+
M = [B] or [Zr]
C (R1 = Me, R2 = β-D-glucose)
R2O
Figure 1 Myxobacterium natural products archazolid A–C
Scheme 1 Archazolid retrosynthesis
V-ATPases play a central role in several aspects of cellu-
lar function, including acidification of intracellular or-
ganelles and regulation of extracellular pH.3 Their
malfunction has been correlated with various diseases
ranging from cancer4 to renal acidosis5 and osteoporosis.6
As potent and selective inhibitors, the archazolids present
an opportunity to study the development of these diseases
and to design drugs for their therapy.
In order to test the allylation–elimination reaction se-
quence, an appropriately functionalized model lactone 113
was partially reduced with DIBAL-H at –78 °C and sub-
sequently treated with the in situ prepared10 TMS-substi-
tuted allylborane reagent 2 (Scheme 2).
After several hours at room temperature the starting mate-
rial was completely consumed, converted to presumably
b-alkoxysilane 3 proceeding through a cyclic chair-like
transition state. Base-induced elimination with NaOEt af-
forded a 2.6:1 (NMR) mixture of 2,3-substituted conju-
gated trienes. The use of different bases such as NaOH or
NaH for the elimination step had no effect on the resulting
stereochemical ratio suggesting that the observed isomer-
ic mixture is determined during the formation of the inter-
mediate b-alkoxysilane. The stereochemistry of the major
product was tentatively assigned as the expected Z,Z-
isomer 4 by chemical shift correlation. In particular, the
The 30-carbon linear polyketide backbone of the arc-
hazolids has been incorporated into a highly functional-
ized 24-membered macrolactone. Extensive NMR
analysis of archazolid A led to the determination of rela-
tive stereochemistry.7 This was later confirmed and the
absolute stereochemistry assigned by total synthesis.8
Embedded within the core is a synthetically challenging
C9–C14 Z,Z,E-conjugated triene unique to the archazolids.
SYNLETT 2010, No. 1, pp 0107–0110
x
x.
x
x.
2
0
1
0
1
Advanced online publication: 02.12.2009
DOI: 10.1055/s-0029-1218537; Art ID: S07709ST
© Georg Thieme Verlag Stuttgart · New York
terminal alkene methine H NMR signal was diagnostic,
appearing consistently downfield for the Z-isomer.14

108
G. W. O’Neil, M. J. Black
LETTER
ride then set the stage for formation of the C9–C10 trisub-
stituted cis-alkene by RCM. After some optimization, it
was found that lactone 12 could be obtained in 65% yield
using 5 mol% Grubbs second-generation catalyst (13)18 in
a dilute (0.01 M) solution of refluxing (110 °C) toluene.
H
O
BBN
1. DIBAL-H, –78 °C
R
O
TMS
O
2
2.
TMS
BBN
1
OH
(δ = 6.55)
H
1. MnO2, Et2O
1. TBSCl, imid.
5
TBSO
OH
4
2. DIBAL-H
2.
(–)-(iPc)2B
70% (2 steps)
9
B
O
H
TMS
Me
NaOEt
72% (2 steps)
+
10
R
72%
(2 steps)
OH
(Z,Z/Z,E = 2.6:1)
3
O
OH
1. pyr.,
O
O
Cl
8
7
TBSO
2.
12
11
N
N
(δ = 6.41)
H
Mes
Mes
TBSO
Cl
Scheme 2
Ru
59% (2 steps)
13
Cl
Ph
PCy3
Encouraged by this result, an application to the archazol-
id-conjugated triene was next investigated. Our synthesis
began with ester 5, prepared as a separable mixture along
with lactone 6 from 4-hydroxy-2-butanone (Scheme 3).15
Scheme 4
Reduction of 12 with DIBAL-H at –78 °C proceeded
cleanly to give an intermediate lactol that was immediate-
ly exposed to the allylation–elimination conditions
(Scheme 5). The best yields and selectivities were ob-
tained using an allylzirconation–elimination sequence.
Consistent with our previous observations, the intermedi-
ate zirconium alkoxide did not eliminate under the reac-
tion conditions. Attempts to purify this intermediate in
order to ascertain its diastereomeric purity resulted in rap-
id anti-Peterson elimination giving tetraene 14. Preferen-
tial formation of the desired Z,Z-conjugated triene was
affected by treatment of the product mixture with NaOEt
affording 15 as an inseparable 4:1 (NMR) mixture of ste-
reoisomers. To test the reactivity of this compound toward
metathesis, exposure of 15 to catalyst 13 in the presence
of an excess of cis-1,4-bisacetylated butenediol 16 gave
upon removal of the acetate diol 17. The stereoisomers
from the allylation–elimination sequence were separable
at this point by flash chromatography marking a comple-
tion of a stereocontrolled synthesis of the C3–C15 fragment
of the archazolids.
O
ref. 15
CO2Me
+
6
HO
HO
5
NOE
O
Me
H
1. DIBAL-H, –78 °C
2.
H
O
HO
7
8
6
TMS
ZrCp2Cl
NOE
then BF3⋅OEt2
H
65% (2 steps)
(Z,E/Z,Z = 2.7:1)
Scheme 3
Lactone 6 was identified as a suitable substrate with
which to investigate the tandem TMS-substituted allyzir-
conation–elimination. Partial reduction of 6 with DIBAL-
H gave an intermediate lactol that was immediately treat-
ed with an in situ prepared11 allylzirconocene 7. In con-
trast to previously described substrates, the intermediate
zirconium alkoxide did not spontaneously undergo a syn-
Peterson-type elimination. This afforded an opportunity
to control the stereochemistry of the newly formed trisub-
stituted alkene by choice of either basic or acidic workup
conditions. For instance, addition of BF3·OEt2 to the reac-
tion mixture resulted in rapid anti-elimination giving
triene 8 as a 2.7:1 (NMR) Z,E/Z,Z mixture of stereoiso-
mers in 65% yield from 6.16
In summary, a tandem lactol allylation–Peterson elimina-
tion reaction sequence has been used to stereoselectively
prepare several substituted conjugated trienes. In contrast
to previously described substrates, intermediate b-silyl
zirconium alkoxides could be selectively converted to
both Z,E- and Z,Z-terminal trienes by acid- or base-
induced elimination, respectively. This method was suc-
cessfully applied to a synthesis of the archazolid-conju-
gated triene subunit. The resulting tetraene underwent a
highly chemoselective cross-metathesis thus completing a
synthesis of the C3–C15 archazolid fragment. Current ef-
forts are directed toward improving the selectivity of the
allylation process through the use of different organome-
tallic reagents and a completion of the archazolid synthe-
sis.
Continuation of the archazolid synthesis from 5 began
with protection of the free hydroxyl as the TBS-ether and
reduction of the ester with DIBAL-H giving allylic alco-
hol 9 in 72% yield over the two steps (Scheme 4). The C7–
C8 anti-propionate was installed by oxidation followed by
crotylation using Brown’s method17 giving compound 11
in 70% yield from 9. Acylation with methacryloyl chlo-
Synlett 2010, No. 1, 107–110 © Thieme Stuttgart · New York

LETTER
Synthesis of the C3–C15 Fragment of the Archazolids
109
anes, 0.53 mL), and the resulting mixture was stirred for 10 min.
The reaction was quenched with aq Rochelle’s salt (15 mL) and
stirred with EtOAc (15 mL) for 30 min. The layers were separated
and the organic phase dried over MgSO4, filtered, and concentrated
in vacuo. The resulting lactol was used without further purification.
NOE
Me
H
H
OH
O
H
R
14
To a suspension of zirconocence hydrochloride (0.47 g, 1.84 mmol)
in CH2Cl2 (6.9 mL) at –78 °C was added 1-methyl-1-(trimethylsi-
lyl)allene (0.46 ml, 2.76 mmol), and the mixture was warmed to r.t.
for 15 min (until a red homogeneous solution developed). To the al-
lylzirconocene thus obtained was added the crude lactol as a solu-
tion in CH2Cl2 (2.3 mL), and the reaction was stirred for 15 h. The
reaction was cooled to 0 °C and BF3·OEt2 (0.17 mL, 1.38 mmol)
was added, and the mixture was stirred for 1 h before diluting with
CH2Cl2 (15 mL) and quenching with aq NaHCO3 (15 mL). The lay-
ers were separated and the organic phase dried over MgSO4, fil-
tered, and concentrated in vacuo. Purification by flash column
chromatography on silica (4:1 hexanes–EtOAc) afforded triene 8
(46 mg, 65%) as an inseparable 2.7:1 (NMR) mixture of E/Z iso-
mers.
NOE
TBSO
H
HO
TMS
2
3
1
O
O
O
H
12
TBSO
TBSO
Z/E = 4:1
15
4
HO
O
O
H
H
17
15
IR (ATR): 3360, 2922, 2852, 1659, 1632, 1461, 1377, 1045, 722
cm–1.
3
TBSO
TBSO
1
Scheme 5 Reagents and conditions: (1) (a) DIBAL-H, CH2Cl2,
–78 °C; (b) 7, CH2Cl2, r.t., (2) SiO2, 42% (2 steps); (3) NaOEt, THF,
r.t., 68% (2 steps); (4) (a) 16, 13 (10 mol%), PhMe, 60 °C; (b)
DIBAL-H, CH2Cl2, 0 °C, 60% (2 steps).
Characteristic signals for the major stereoisomer: H NMR (500
MHz, CDCl3): d = 6.44 (dd, J = 17.1, 10.7 Hz, 1 H), 6.33 (d,
J = 11.7 Hz, 1 H), 6.28 (d, J = 11.7 Hz, 1 H), 5.19 (d, J = 17.1 Hz,
1 H), 5.01 (d, J = 10.8 Hz, 1 H), 3.76–3.70 (m, 2 H), 2.51 (t, J = 6.8
Hz, 2 H), 1.89 (s, 3 H), 1.85 (s, 3 H). 13C NMR (75 MHz, CDCl3):
d = 141.6, 126.8, 124.6, 111.9, 60.9, 35.6, 35.3, 24.6, 24.4, 11.8.
HRMS (ESI+): m/z calcd for C10H16ONa [M + Na]+: 174.1021;
found: 174.1032.
Allylboration–syn-Elimination Sequence for the Synthesis of
Compound 4
To a solution of lactone 1 (50 mg, 0.27 mmol) in CH2Cl2 (2.7 mL)
at –78 °C was added dropwise a solution of DIBAL-H (1.0 M hex-
anes, 0.27 mL), and the resulting mixture was stirred for 10 min.
The reaction was quenched with aq Rochelle’s salt (10 mL) and
stirred with EtOAc (10 mL) for 30 min. The layers were separated
and the organic phase dried over MgSO4, filtered, and concentrated
in vacuo. The resulting lactol was used without further purification.
Allylzirconation–syn-Elimination Sequence for the Synthesis of
Compound 15
To a solution of lactone 12 (56 mg, 0.17 mmol) in CH2Cl2 (1.7 mL)
at –78 °C was added dropwise a solution of DIBAL-H (1.0 M hex-
anes, 0.204 mL), and the resulting mixture was stirred for 10 min.
The reaction was quenched with aq Rochelle’s salt (15 mL) and
stirred with EtOAc (15 mL) for 30 min. The layers were separated
and the organic phase was dried over MgSO4, filtered, and concen-
trated in vacuo. The resulting lactol was used without further puri-
fication.
To a solution of 1-methyl-1-(trimethylsilyl)allene (0.134 mL, 0.80
mmol) in THF (1.6 mL) at r.t. was added a 9-BBN solution (1.0 M
THF, 0.80 mL), and the resulting mixture was stirred for 2 h. To the
allylborane thus obtained at 0 °C was added the crude lactol as a so-
lution in THF (1.6 mL), and the reaction was allowed to slowly
warm to r.t. overnight. The reaction was cooled to 0 °C and NaOEt
(216 mg, 3.24 mmol) was added, and the mixture was stirred for 1
h before diluting with Et2O (15 mL) and washing with aq NH4Cl (15
mL). The layers were separated and the organic phase dried over
MgSO4, filtered, and concentrated in vacuo. Purification by flash
column chromatography on silica (10:1 to 4:1 hexanes–EtOAc) af-
forded triene 4 (44 mg, 72%) as an inseparable 2.6:1 (NMR) mix-
ture of Z/E isomers.
To a suspension of zirconocence hydrochloride (0.177 g, 0.69
mmol) in CH2Cl2 (1.7 mL) at –78 °C was added 1-methyl-1-(trime-
thylsilyl)allene (0.17 mL, 1.03 mmol), and the mixture was warmed
to r.t. for 15 min (until a red homogeneous solution developed). To
the allylzirconocene thus obtained was added the crude lactol as a
solution in CH2Cl2 (0.86 mL), and the reaction was stirred for 15 h.
The reaction was quenched with aq NaHCO3 (15 mL) and extracted
with CH2Cl2 (2 × 15 mL). The combined organic extracts were
dried over MgSO4, filtered, and concentrated in vacuo. The crude
product was redissolved in THF (1.7 mL) at 0 °C, NaOEt was added
(0.14 g, 2.04 mmol), and the mixture was warmed to r.t. for 1 h be-
fore diluting with MTBE (15 mL) and washing with aq NH4Cl (15
mL). The layers were separated and the organic phase dried over
MgSO4, filtered, and concentrated in vacuo. Purification by flash
column chromatography on silica (4:1 hexanes–EtOAc) afforded
tetraene 15 (42 mg, 68%) as an inseparable 4.0:1 (NMR) mixture of
Z/E isomers.
IR (ATR): 3320, 2937, 1496, 1453, 1029, 917, 742 cm–1.
1
Characteristic signals for the major stereoisomer: H NMR (500
MHz, CDCl3): d = 7.35–7.31 (m, 5 H), 6.54 (ddd, J = 17.6, 10.6, 0.7
Hz, 1 H), 5.74 (s, 1 H), 5.36 (m, 1 H), 5.22 (ddd, J = 17.6, 1.5, 0.8
Hz, 1 H), 5.08 (dt, J = 10.6, 1.8 Hz, 1 H), 4.69 (dd, J = 7.7, 5.1 Hz,
1 H), 2.45–2.32 (m, 2 H), 1.86 (d, J = 1.5 Hz, 3 H), 1.78 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 144.2, 135.8, 135.4, 129.5, 128.4,
128.3, 127.4, 125.9, 123.7, 114.3, 74.1, 39.0, 24.4, 19.3. HRMS
(CI+): m/z calcd for C16H20OH+ [M + H]+: 229.1592; found:
229.1571.
20
[a]D –6.6 (c 0.5, CH2Cl2). IR (ATR): 2988, 2970, 1631, 1604,
1505, 1437, 1391, 1229, 1029, 896, 854, 826 cm–1.
1
Characteristic signals for the major stereoisomer: H NMR (500
MHz, CDCl3): d = 6.63 (ddd, J = 11.6, 10.7, 0.6 Hz, 1 H), 5.85 (s, 1
H), 5.21 (ddd, J = 17.6, 1.4, 0.8 Hz, 1 H), 5.20–5.15 (m, 2 H), 5.08
(dt, J = 10.7, 1.4 Hz, 1 H), 4.02 (t, J = 8.8 Hz, 1 H), 3.68 (t, J = 7.2
Hz, 2 H), 2.33 (m, 1 H), 2.27–2.18 (m, 2 H), 1.87 (d, J = 1.4 Hz, 3
H), 1.82 (s, 3 H), 1.69 (d, J = 1.4 Hz, 3 H), 0.88 (s, 9 H), 0.86 (d,
Allylzirconation–anti-Elimination Sequence for the Synthesis of
Compound 8
To a solution of lactone 6 (50 mg, 0.46 mmol) in CH2Cl2 (4.6 mL)
at –78 °C was added dropwise a solution of DIBAL-H (1.0 M hex-
Synlett 2010, No. 1, 107–110 © Thieme Stuttgart · New York

110
G. W. O’Neil, M. J. Black
LETTER
J = 6.9 Hz, 3 H), 0.04 (s, 6 H). 13C NMR (75.5 MHz, CDCl3): d =
136.9, 135.2, 135.1, 133.9, 130.9, 129.5, 127.4, 114.2, 72.2, 62.1,
43.0, 10.5, 25.9, 24.7, 19.4, 18.3, 17.3, 16.1, –5.3. HRMS (CI+):
m/z calcd for C22H40O2Si: 364.2798; found: 364.2827.
(6) Schlesinger, P. H.; Blair, H. C.; Teitelbaum, S. L.; Edwards,
J. C. J. Biol. Chem. 1997, 272, 18636.
(7) Hassfeld, J.; Farès, C.; Steinmetz, H.; Carlomagno, T.;
Menche, D. Org. Lett. 2006, 8, 4751.
(8) (a) Menche, D.; Hassfeld, J.; Li, J.; Rudolph, S. J. Am.
Chem. Soc. 2007, 129, 6100. (b) Roethle, P. A.; Chen, I. T.;
Trauner, D. J. Am. Chem. Soc. 2007, 129, 8960.
(9) Huang, Z.; Negishi, E. J. Am. Chem. Soc. 2007, 129, 14788.
(10) Wang, K. K.; Chin, L.; Yu, G.; Burnett, F. J. Org. Chem.
1991, 56, 1914.
(11) Huang, X.; Pi, J.-P. Tetrahedron Lett. 2004, 45, 2215.
(12) Hudrlik, P. F.; Peterson, D. J. Am. Chem. Soc. 1975, 97,
1464.
(13) Chen, C.-C.; Fan, J.-S.; Lee, G.-H.; Peng, S.-M.; Wang,
S.-L.; Liu, R.-S. J. Am. Chem. Soc. 1995, 117, 2933.
(14) The stereochemistry was later confirmed by NMR analysis.
See Supporting Information for details.
(15) White, J. D.; Carter, P.; Kezar, H. S. J. Org. Chem. 1982, 47,
929.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
Financial support from Western Washington University, M.J.
Murdoch Charitable Trust, and Research Corporation departmental
development grant is gratefully acknowledged.
References and Notes
(1) (a) Sasse, F.; Steinmetz, H.; Höfle, G.; Reichenbach, H.
J. Antibiot. 2003, 56, 520. (b) Menche, D.; Hassfeld, J.;
Steinmetz, H.; Huss, M.; Wieczorek, H.; Sasse, F. Eur. J.
Org. Chem. 2007, 1196.
(2) Huss, M.; Sasse, F.; Kunze, B.; Jansen, R.; Steinmetz, H.;
Ingenhorst, G.; Zeeck, A.; Wieczorek, H. BMC Biochem.
2005, 6, 13.
(16) A similar conjugated triene product was obtained with
comparable yield and selectivity from an acyclic substrate
(Scheme 6); see Supporting Information for details.
(3) Wieczorek, H.; Brown, D.; Grinstein, S.; Ehrenfeld, J.;
7 then
Harvey, W. R. Bioessays 1999, 21, 637.
(4) Sennoune, S. R.; Luo, D.; Martinez-Zaguilan, R. Cell
Biochem. Biophys. 2004, 40, 185.
BF3⋅OEt2
CHO
(5) Karet, F. E.; Finberg, K. E.; Nelson, R. D.; Nayir, A.;
Mocan, H.; Sanjad, S. A.; Rodriguez-Soriano, J.; Santos, F.;
Cremers, C.; Di Pietro, A.; Hoffbrand, B. I.; Winiarski, J.;
Bakkaloglu, A.; Ozen, S.; Dusunsel, R.; Goodyer, P.;
Hultons, S. A.; Wu, D. K.; Skvorak, A. B.; Morton, C. C.;
Cunningham, M. J.; Jha, V.; Lifton, R. P. Nat. Genet. 1999,
21, 84.
Scheme 6
(17) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108,
5919.
(18) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
Synlett 2010, No. 1, 107–110 © Thieme Stuttgart · New York

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