Titanium(II)-mediated cyclization of (silyloxy)enynes: A synthesis of the C9-C19 subunit of dictyostatin-1

Article abstract of DOI:10.1016/j.tetlet.2004.04.018

Cyclization of (silyloxy)enynes with ClTi(i-PrO)₃ and i-PrMgCl gives cyclic siloxanes. This cyclization offers a new approach to mixed polyacetate-polypropionate polyketides, and has been applied to the synthesis of the C9-C19 subunit of dictyostatin-1.

Full text of DOI:10.1016/j.tetlet.2004.04.018

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4253–4256
Titanium(II)-mediated cyclization of (silyloxy)enynes:
a synthesis of the C9–C19 subunit of dictyostatin-1
Gregory W. O’Neil and Andrew J. Phillips*
Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309-0215, USA
Received 18 March 2004; revised 4 April 2004; accepted 6 April 2004
Abstract—Cyclization of (silyloxy)enynes with ClTi(i-PrO)3 and i-PrMgCl gives cyclic siloxanes. This cyclization offers a new
approach to mixed polyacetate-polypropionate polyketides, and has been applied to the synthesis of the C9–C19 subunit of dict-
yostatin-1.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Dictyostatin-1 (Fig. 1) is a marine-derived macrolide
that was first isolated by Pettit et al. from a Spongia sp.
marine sponge collected in the Republic of Maldives.1
Dictyostatin-1 displays potent growth inhibition of the
P388 murine leukemia cell line (ED50 0.38 ng mLꢀ1),
along with differential cytotoxicity in the NCI 60-cell
line screen with sub-nanogram per milliliter ED50 values
against other cancer cell lines such as NCI H460non-
small cell lung, KM 20L2 colon, SF-295 CNS, SK-
MEL5 melanoma, OVCAR-3 ovarian, and A-498 renal.
two very important features of dictyostatin-1’s biologi-
cal profile: (i) it inhibits cell growth by the same mech-
anism of action as paclitaxel (tubulin polymerization),
and (ii) it demonstrates potent activity against paclit-
axel-resistant lines such as MCF-7/ADR and MES-SA/
DX5.
Because of dictyostatin-1’s potent biological activity,
and limited supply from the natural source,2 we have
embarked on a total synthesis of dictyostatin-1. In
considering a strategy for the synthesis of dictyostatin-1,
we were attracted to the possibility of exploiting the
cyclization of enynes by group 4 metals as a new
approach to cyclic siloxanes (Scheme 1). We envisaged
that cyclic siloxanes would provide versatile templates
for the synthesis of the C1–C7, C9–C13, and C21–C26
regions of dictyostatin-1.
Recent research at the Harbor Branch Oceanographic
Institute described the isolation of dictyostatin-1 from a
Corallistidae sp. lithistid sponge.2 This material was
used to assign the stereochemistry of dictyostatin-13 and
also allowed further preliminary testing that illustrated
Five-membered cyclic siloxanes are traditionally syn-
thesized4 by intramolecular hydrosilylation of homo-
propargyl alkynols, radical additions to tethered alkynyl
silanes, ring opening of alkylidenesiliranes, or silyl-
formylation of alkynes, and have proven to be useful
intermediates for the synthesis of a variety of polyketide
functional group arrays.5 In this Letter we describe our
H
O
26
16
7
19
HO
21
12
Dictyostatin-1
O
O
1
9
OH OH
Figure 1. Dictyostatin-1.
R3
R3
O
R3
Si
O Si R3
Ti(II)-mediated
R2
R2
enyne cyclization
R
R
Keywords: Total synthesis; Dictyostatin; Enyne cyclization.
* Corresponding author. Tel.: +1-303-735-2049; fax: +1-303-492-0439;
e-mail: andrew.phillips@colorado.edu
Scheme 1. Synthesis of cyclic siloxanes by titanium(II)-mediated enyne
cyclization.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.018

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G. W. O’Neil, A. J. Phillips / Tetrahedron Letters 45 (2004) 4253–4256
Table 1. Reagents and conditions: ClTi(i-PrO)3, i-PrMgCl, Et2O,
Pri
O
Pri
Pri
OH
Si
)40 ꢁC
O Si Pri
a
b
Ph
Entry
Substrate
Product
Yield (%)
58
Ph
Ph
Pri
O
Pri
Pri
1
2
3
Si
O
Si Pri
1
Me
Me
Scheme 2. Reagents and conditions: (a) bromodiisopropylpropynyl-
silane, DMAP, DMF, quantitative; (b) ClTi(i-PrO)3, i-PrMgCl, Et2O,
)40 ꢁC, 65%.
4
Pri
O
Pri
Pri
O
Si
Si Pri
2
3
57
57
preliminary studies on a new synthesis of cyclic siloxanes
based on a Ti(II)-mediated cyclization of (silyloxy)eny-
nes, along with the successful application of this reaction
to the synthesis of the C9–C19 subunit of dictyostatin-1.
OTBS
OTBS
Ph
Ph
5
Pri
O
Pri
Pri
O
Si
Si Pri
nBu
nBu
nBu
nBu
Our initial studies focused on readily accessible (silyl-
oxy)enyne 2, which was prepared by silylation of alcohol
1 with bromodiisopropylpropynylsilane (Scheme 2).6
While a variety of reagents such as Pd(0), Zr(II), and
other sources of Ti(II) were not suitable, we were
pleased to discover that the desired cyclization could be
effected with (g2-propene)Ti(i-PrO)2 generated in situ
from ClTi(i-PrO)3 and i-PrMgCl at )40 ꢁC.7 Under
these conditions 2 was cyclized to produce 3 as a single
diastereoisomer in 65% yield.8
6
Pri
O
Pri
Pri
Pri
O
Si
Si Pri
4
58
Ph
Ph
7
Pri
O
Pri
O
Si
Si Pri
5
6
OTBS 56
OTBS
8
Pri
O
Pri
Pri
Pri
Si
Si
TIPSO
TIPSO
O
Si Pri
TIPSO
TIPSO
53
Further examples that illustrate the scope of this trans-
formation are presented in Table 1.9;10 As can be seen
from the table a variety of systems are suitable as sub-
strates, and the reaction produces exclusively the anti
diastereoisomer.11 It is noteworthy that the reaction can
be applied to the synthesis of syn,anti- and anti,anti-
stereotriads (entries 6 and 7 to produce compounds 9
and 10, respectively).
nBu
nBu
9
Pri
O
Pri
O
Si Pri
7
58
nBu
nBu
10
With conditions for the cyclization of (silyloxy)enynes
established, we turned our attention to utilizing this
transformation for the synthesis of the alkenyl substi-
tuted C9–C14 stereotriad of dictyostatin-1.12 The
synthesis began with the Myers alkylation13 of
pesudoephedrine derived amide 11 with iodide 12, and
subsequent reduction with lithium amidotrihydroborate
OH
N
Ph
OPMB
O
a
b
OPMB
11
+
HO
O
HO
13
14
I
OPMB
HO
12
OPMB
OPMB
c
e
d
O
i-Pr2Si
15
16
OPMB
OPMB
OPMB
f
g
O
O
O
O
O
i-Pr2Si
17
18
19
Scheme 3. Reagents and conditions: (a) (1) LDA, LiCl; (2) LiH2NBH3, 65% (two steps); (b) (1) Dess–Martin then Ph3PCHCO2Et; (2) DIBAL-H;
(3) ())-DIPT, Ti(i-PrO)4, TBHP, 56% (three steps); (c) I2, Ph3P, imidazole then t-BuLi, 85%; (d) bromodiisopropylpropynylsilane, DMAP, DMF,
€
95%; (e) ClTi(i-PrO)3, i-PrMgCl, 59%; (f) (1) TBAF, THF; (2) acryloyl chloride, Hunig’s base, DMAP, 62% (two steps); (g) 5%
(H2IMes)(PCy3)(Cl)2Ru@CHPh, PhH, 60 ꢁC, 85%.

G. W. O’Neil, A. J. Phillips / Tetrahedron Letters 45 (2004) 4253–4256
4255
(LAB)14 to give alcohol 13 in 65% yield over the two
steps (Scheme 3). Alcohol 13 was advanced to epoxy
alcohol 14 by a three-step sequence (56% overall yield)
consisting of: (a) Dess–Martin oxidation–Wittig olefin-
ation; (b) DIBAL reduction, and (c) Sharpless asym-
metric epoxidation. Installation of the allylic alcohol
was achieved by conversion of this alcohol to the iodide,
followed by immediate reaction with tert-BuLi15 to
provide allylic alcohol 15 in 85% yield. Subsequent
silylation of alcohol 15 with bromo diisopropylpropynyl-
silane led to (silyloxy)enyne 16 in 95% yield. Treatment
of a solution of 16 and ClTi(i-PrO)3 with i-PrMgCl
under conditions established in our preliminary studies
produced cyclic siloxane 17 in 59% yield as a single
diastereoisomer. Removal of the silicon (TBAF) and
acylation with acryloyl chloride (65% over two steps,
17 fi 18), followed by ring-closing metathesis with
Grubbs’ (H2IMes) (PCy3)(Cl)2Ru@CHPh catalyst16
provided lactone 19 in 85% yield, and completed the
synthesis of the C9–C19 subunit of dictyostatin-1.
F. Acc. Chem. Res. 2002, 35, 835; (d) Denmark, S. E.;
Kobayashi, T. J. Org. Chem. 2003, 68, 5153.
6. Synthesized from propynyllithium by silylation with
chlorodiisopropylsilane and subsequent bromination with
NBS (98% yield over two steps). The other bromo
diisopropylalkynylsilanes were generated by the same
approach. Silylation of the appropriate allylic alcohols
with bromo diisopropylalkynylsilanes proceeds in >95%
yields to provide the (siloxy)enynes for cyclization. Details
will be reported in a full paper.
7. To the best of our knowledge the cyclization of (silyl-
oxy)enynes by Ti(II) or Zr(II) reagents to produce cyclic
siloxanes is not known. For recent reviews of the
chemistry of these species see: (a) Sato, F.; Okamoto, S.
Adv. Synth. Cat. 2001, 343, 759; (b) Kulinkovich, O. G.; de
Meijere, A. Chem. Rev. 2000, 100, 2789; (c) Sato, F.;
Urabe, H.; Okamoto, S. Chem. Rev. 2000, 100, 2835.
8. Analysis of 1H NMR spectra of the crude reaction mixture
showed only a single diastereoisomer. The stereochemistry
3
is readily assigned by coupling constant analysis. JH;H
values for cyclic siloxanes with an anti relationship
between the oxygen and methyl bearing carbons are
typically between 8.8–10.2 Hz, which is consistent with /
values of ꢁ170ꢁ.
In summary, we have demonstrated that (silyloxy)eny-
nes can be cyclized by in situ generated (g2-pro-
pene)Ti(i-PrO)2. The reaction proceeds with excellent
diastereoselectivity to provide cyclic siloxanes with an
anti relationship between the oxygen and methyl bearing
carbons. Mechanistic studies are ongoing, and further
applications of this transformation to the synthesis of
dictyostatin-1 will be reported in due course.
Pri
O Si Pri
H
R
R2
3JH,H = 8.8 - 10.2 Hz
H
This was further confirmed by desilylation of 3 with TBAF
to provide the known 1,2-anti 2-methyl-1-phenyl-pent-3-
en-1-ol (Andersen, M.; Hildebrandt, B.; Koester, G.;
Hoffmann, R. W. Chem. Ber. 1989, 122, 1777). The ste-
reochemistry of all other products was assigned by similar
approaches.
Acknowledgements
9. All new compounds were fully characterized by 1H and
13C NMR, HRMS, and IR.
10. Representative experimental procedure: i-PrMgCl (800 lL
of a 1.6 M solution in Et2O, 1.28 mmol) was added by
syringe pump over a period of 2 h to a solution of
silyloxyenyne 16 (98 mg, 0.21 mmol) and ClTi(i-PrO)3
(167 mg, 0.64 mmol) in Et2O (3 mL) at )40 ꢁC. After
addition of the i-PrMgCl was complete, the reaction was
stirred at )40 ꢁC for further 4 h before being quenched
with i-PrOH. The reaction was diluted with Et2O, washed
with saturated aqueous NH4Cl solution, filtered through
Celiteꢂ, dried with MgSO4, and evaporated to leave an oil
that was chromatographed on SiO2 gel with 10% Et2O in
hexanes to yield 17 (58 mg, 59%). 1H NMR (CDCl3,
500 MHz): 1H NMR (500 MHz) d 0.8–1.08 (m, 31H), 1.76
(dd, 3H, J ¼ 3:5, 8.5 Hz), 2.25 (m 1H), 3.27 (dd, 1H,
J ¼ 2:5, 12 Hz), 3.43 (m, 2H), 3.80(s, 3H), 4.43 (s, 2H),
6.08 (qd, 1H, J ¼ 3, 8 Hz), 6.87 (d, 2H, J ¼ 11 Hz) 7.26 (d,
2H, J ¼ 11 Hz). 13C NMR (400 MHz) d 12.94, 13.43,
13.57, 15.12, 17.72, 17.77, 17.84, 18.33, 20.34, 20.79, 27.43,
29.98, 32.58, 33.58, 42.22, 42.47, 55.50, 70.86, 72.71, 85.62,
113.95, 129.45, 131.05, 131.69, 143.21, 159.28. HRMS
(ESI): calcd. for C28H48O3Si (M + Hþ) 461.3445, found
461.3448.
11. Further mechanistic studies will be required to establish
the source of the observed diastereoselectivity.
12. Curran, Day, and co-workers have described the synthesis
of discodermolide-dictyostatin-1 hybrids: Shin, Y.; Choy,
N.; Turner, T. R.; Balachandran, R.; Madiraju, C.; Day,
B. W.; Curran, D. P. Org. Lett. 2002, 4, 4443.
13. Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.;
Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997,
119, 6496.
We thank the University of Colorado for support of this
research.
References and notes
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