Total synthesis of spirotryprostatin B via diastereoselective prenylation

Article abstract of DOI:10.1021/ol070971k

Spirotryprostatin B was synthesized in eight steps, utilizing an efficient palladium-catalyzed prenylation reaction to construct the quaternary C3 stereocenter. The decarboxylation-alkylation of a series of substituted β-keto esters is described, demonstr

Full text of DOI:10.1021/ol070971k

ORGANIC
LETTERS
2
007
Vol. 9, No. 15
763-2766
Total Synthesis of Spirotryprostatin B
via Diastereoselective Prenylation
2
Barry M. Trost* and Dylan T. Stiles
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-0508
bmtrost@stanford.edu
Received April 25, 2007
ABSTRACT
Spirotryprostatin B was synthesized in eight steps, utilizing an efficient palladium-catalyzed prenylation reaction to construct the quaternary
C3 stereocenter. The decarboxylation−alkylation of a series of substituted
â
-keto esters is described, demonstrating the broad scope of this
class of pronucleophiles and allylating agents.
4
In an endeavor to identify natural products capable of
regulating specific stages of the cell cycle, Osada et al.
isolated spirotryprostatins A (1) and B (2) from the fermen-
syntheses of 2 have been reported, motivated in part by its
scarce natural abundance (11 mg from a 400 L fermentation)
and its unique structure. The scaffold of spirotryprostatin B
has recently served as the blueprint for a library of cellular
5
probes.
The most synthetically challenging structural features in
2
are the spirocyclic ring juncture at C3 and the adjacent
prenyl-substituted C18. Our approach to spirotryprostatin B
involves the construction of the C3 quaternary stereocenter
in a highly controlled mannersa feat that has proven difficult
in prior syntheses. Approaches toward 2 that generate the
spirocyclic stereocenter by using substrate control, e.g., using
4
c,i
Mannich-type processes, typically result in a mixture of
Figure 1. Spirotryprostatin A (1) and spirotryprostatin B (2).
(
3) (a) Yamazaki, M.; Fujimoto, H.; Kawasaki, T. Chem. Pharm. Bull.
1
980, 28, 245-254. (b) Hino, T.; Nakagawa, M. Heterocycles 1997, 46,
tation broth of Aspergillus fumigatus in 1996.1 These
compounds inhibit the G2/M phase of the mammalian cell
cycle at micromolar concentrations. Biosynthetically, 1 and
673-704.
(4) (a) Overman, L. E.; Rosen, M. D. Angew. Chem., Int. Ed. 2000, 39,
4
596-4599. (b) Sebahar, P. R.; Williams, R. M. J. Am. Chem. Soc. 2000,
122, 5666-5667. (c) von Nussbaum, F.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 2000, 39, 2175-2178. (d) Wang, H.; Ganesan, A. J. Org. Chem.
2
likely derive from the diketopiperazine of tryptophan and
2000, 65, 4685-4693. (e) Sebahar, P. R.; Osada, H.; Usui, T.; Williams,
2
proline, a motif also found in the tryprostatin and fumi-
tremorgin3 families of natural products. A number of
R. M. Tetrahedron 2002, 58, 6311-6322. (f) Bagul, T. D.; Lakshmaiah,
G.; Kawabata, T.; Fuji, K. Org. Lett. 2002, 4, 249-251. (g) Meyers, C.;
Carreira, E. M. Angew. Chem., Int. Ed. 2003, 42, 694-696. (h) Marti, C.;
Carreira, E. M. Eur. J. Org. Chem. 2003, 2209-2219. (i) Miyake, F. Y.;
Yakushijin, K.; Horne, D. A. Angew. Chem., Int. Ed. 2004, 43, 5357-
5360. (j) Marti, C.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 11505-
11515.
(
1) (a) Cui, C. B.; Kakeya, H.; Osada, H. J. Antibiot. 1996, 49, 832-
8
1
35. (b) Cui, C. B.; Kakeya, H.; Osada, H. Tetrahedron 1996, 52, 12651-
2666.
(
2) Cui, C. B.; Kakeya, H.; Okada, G.; Onose, R.; Ubukata, M.;
(5) Lo, M. M.-C.; Neumann, C. S.; Nagayama, S.; Perlstein, E. O.;
Schreiber, S. L. J. Am. Chem. Soc. 2004, 126, 16077-16086.
Takahashi, I.; Isono, K.; Osada, H. J. Antibiot. 1995, 48, 1382-1384.
1
0.1021/ol070971k CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/26/2007

diasteromeric products, resulting in a low overall yield for
this relatively simple natural product. While this problem
has been addressed with the use of stoichiometric chiral
auxiliaries, there has been only one report of a strategy that
invokes asymmetric catalysis to forge the C3 spirocenter,
to allyl or 2-substituted allyl groups. Going beyond such
limited substrates would be an important step in enhancing
the utility of this methodology. Therefore we have undertaken
an examination of systems with trisubstituted olefins such
as prenyl, presented here in the context of a natural product
synthesis.
The type of anion depicted in 4 also poses the challenge
of control of regioselectivity. Compound 4 features two
nucleophilic sites (the oxindole and diketopiperazine car-
bons), making eight potential isomeric products. We desire
the product arising from decarboxylative allylation with
double bond transposition, which has not previously been
reported.
4a
although the route ultimately proved to be rather long. The
4
c
shortest route exercises no stereocontrol at any step.
Retrosynthetically, we envision that 2 can derive from the
functionalization of 3 (Figure 2), which raises the question
A rapid synthesis of 5 was accomplished starting with Cbz-
proline and dimethyl aminomalonate hydrochloride (Scheme
15
1
). Known diketopiperazine 8 was transesterified to prenyl
Scheme 1. Synthesis of Prenylation Substrate
Figure 2. Retrosynthetic analysis.
of whether a prenyl chain can be introduced via palladium-
catalyzed allylic alkylation. The required nucleophile 4 is a
stabilized carbanion that can be thought of as a vinylogous
1,3-dicarbonyl species. As the location of the double bond
in 4 is presumably labile, a number of compounds could
potentially serve to generate the same reactive intermediate.
We ultimately targeted the use of ester 5 as a nucleo-
phile precursor. Upon exposure to palladium catalysis, 5
would potentially ionize and decarboxylate, triggering the
prenylation reaction.
The decarboxylation-alkylation of 5 is related to the
6
,7
Carroll reaction of allyl-â-ketoesters. While this reaction
was originally conducted by thermolysis, Saegusa and Tsuji
8
9
16
ester 9 with use of Otera’s catalyst. In a one-pot reaction,
17
demonstrated that it could be catalyzed by palladium at much
lower temperatures. More recently, enantioselective variants
have been developed by our group10 and others.11,12
Reports of palladium-catalyzed decarboxylation-alkyla-
tion using phosphinooxazoline (PHOX) ligands pioneered
oxindole 11 was activated as its vinyl tosylate, then treated
with the lithium salt of 9. The coupled product 5 was
obtained in good yield as a 1:1.7 mixture of diastereomers,
a stereogenic center that is later destroyed and subsequently
reconstituted.
18
13
14
by Williams and Pfaltz and Helmchen have been limited
(
15) (a) Kametani, T.; Kanaya, N.; Ihara, M. J. Chem. Soc., Perkin Trans.
1
1981, 959-963. (b) Kardassis, G.; Brungs, P.; Steckhan, E. Tetrahedron
(
(
(
6) Carroll, M. F. J. Chem. Soc. 1940, 1266-1268.
1998, 54, 3471-3478.
7) Kimel, W.; Cope, A. C. J. Am. Chem. Soc. 1943, 65, 1992-1998.
(16) (a) Otera, J.; Dan-oh, N.; Nozaki, H. J. Org. Chem. 1991, 56, 5307-
8) Tsuda, T.; Chujo, Y.; Nishi, S.-I.; Tawara, K.; Saegusa, T. J. Am.
5
311. (b) Otera, J. Chem. ReV. 1993, 93, 1449-1470. The isothiocyanate
Chem. Soc. 1980, 102, 6381-6384.
9) (a) Tsuji, J. Pure Appl. Chem. 1982, 54, 197-206. (b) Tsuji, J.;
Yamada, T.; Minami, I.; Yuhara, M.; Nisar, M.; Shimizu, I. J. Org. Chem.
987, 52, 2988-2995.
10) (a) Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 2846-2847.
b) Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 17180-17181.
11) (a) Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126,
5044-15045. (b) Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B.
catalyst pictured below was used:
(
1
(
(
(
1
(17) Wenkert, E.; Bhattacharyya, N. K.; Reid, T. L.; Stevens, T. E. J.
Am. Chem. Soc. 1956, 78, 797-801.
(18) The E/Z configuration of oxindole-bound olefin in 5 and its
derivatives is not known, but presumed to be as depicted based on known
trends of R,â-unsaturated amides.
M. Angew. Chem., Int. Ed. 2005, 44, 6924-6927.
(
(
(
12) Burger, E. C.; Tunge, J. A. Org. Lett. 2004, 6, 4113-4115.
13) Williams, J. M. Synlett 1996, 705-710.
14) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336-345.
2764
Org. Lett., Vol. 9, No. 15, 2007

With the key substrate in hand, 5 was subjected to
palladium catalysis. We were pleased to find that prenylation
indeed occurred, giving the desired isomer 3 as the major
product. A screening of reaction conditions (Table 1)
Scheme 2. Synthesis of Spirotryprostatin B
Table 1. Selected Optimization Studiesa
aluminum amide, generated in situ by the treatment of 16
with trimethylaluminum, does succeed in promoting the
cyclization to give spirotryprostatin B in 45% isolated yield
b
entry ligand solvent mol % Pd dr of 3 3:15 yield (%)
20
along with minor amounts of isomers 17 and 18. The
1
2
3
4
5
6
7
8
PPh3 dioxane
10
10
10
10
10
2
1:1
2.4:1
2.6:1
8.8:1
16:1
9:1
1.2:1
4.5:1
1.4:1
10:1
14:1
1.3:1
89
83
69
75
89
71
71
0
effectiveness of this reagent can be attributed to its dual role
as both a Brønsted base and a Lewis acid.
Having completed the synthesis of the natural product, we
decided to explore the key allylic alkylation in more detail
12
12
12
12
12
13
14
dioxane
DCE
toluene
toluene
toluene
toluene
THF
c
e
d
(Table 2). Compounds 19-21, bearing a variety of allylic
10
10
1:1.7 11:1
a
Table 2. Allylic Alkylation with Various Substratesa
Unless otherwise indicated, all reactions were conducted at 60 °C on
a 24 µmol scale at 24 µM with Pd2(dba)3‚CHCl3 as a catalyst precursor.
b
Based on NMR relative to N-methylformanilide as an internal standard.
c
Reaction conducted on a 300 mg scale. Isolated yield. e Reaction
d
conducted at 50 °C.
determined that the best results were obtained with ligand
12 in toluene at 60 °C (entries 4 and 5).
The use of triphenylphosphine gave essentially a statistical
mixture of product isomers, highlighting the need for
asymmetric catalysis. The catalyst loading could be lowered
to 2 mol % palladium (entry 6), but the regioselectivity was
diminished. Entry 7 shows that the use of (R,R)-13 is
stereochemically mismatched. When the two diastereomers
of 5 were separated and reacted individually, a similar
product mixture was obtained in each case. These results
support the notion that the reaction proceeds through
common intermediate 4. Therefore, it was more convenient
to carry 5 through the synthesis as a mixture of isomers.
We were pleased to find that the prenylation reaction gave
even better results (dr ) 16:1, regioselectivity ) 14:1) on a
larger scale (300 mg), affording 3 in 89% isolated yield.
To functionalize the prenyl chain and complete the
synthesis (Scheme 2), we turned to selenium chemistry
a
All reactions were conducted at 60 °C on a 24 µmol scale at 24 µM at
b
6
0 °C with Pd2(dba)3‚CHCl3 as a catalyst precursor. Absolute stereo-
chemistry assigned by analogy to 3. Isolated yields. d Reaction run at 40
c
°
C.
substituents, were synthesized in a manner analogous to 5.
As a means to obviate the selenium step, we imagined
introducing the side chain at a higher oxidation state. Thus,
vinyl chloride 21 was prepared.
With all substrates, the reaction proceeded with alkylation
primarily at the oxindole carbon. Nucleophilic attack oc-
curred at the more sterically accessible terminus of the Pd-
allyl intermediate, giving linear products in all cases.
19
originally developed by Sharpless. In one operation, 3 was
first treated with PhSeOAc (prepared in situ), and then the
selenide was oxidized and eliminated with hydrogen perox-
ide, giving the allylic acetate 16 in excellent yield.
For the final cyclization, a survey of conditions using
catalytic palladium or copper failed. However, the use of an
(20) The formation of 18 (12-epi-2) can be attributed to the basicity of
the reaction conditions. This stereocenter has been shown to be labile, e.g.,
ref 4e.
(19) Sharpless, K. B.; Lauer, R. F. J. Org. Chem. 1974, 39, 429-430.
Org. Lett., Vol. 9, No. 15, 2007
2765

Therefore, vinyl chloride 23 was not useful for further
elaboration to 2. The “reversed ester” 19 also functioned.
Although the dr was somewhat reduced compared to 5, good
regioselectivity was observed.
able steric clash between the wall and the geminal dimethyl
substituents of the prenyl group may force rapid collapse of
the ion pair, giving the kinetic product 3. A slower reaction
may allow the Pd-bound prenyl to equilibrate its position
on the catalyst, giving reduced selectivity. This notion is
supported by the diminished regioselectivity observed in a
reaction with 2 mol % palladium catalyst (Table 1, entry 6).
In conclusion, we have developed a rapid synthesis of
spirotryprostatin B that delivers the natural product in 8 steps
and 13% overall yield. The decarboxylation-prenylation of
We propose a model for this reaction depicted in Figure
3
.21 In our standard “wall and flap” depiction of the ligand/
5, with transposition of the double bond, is an unprecedented
transformation. The exquisite control in the formation of the
quaternary C3 stereocenter presents a major improvement
in the synthesis of this family of alkaloids.
Acknowledgment. We thank the National Science Foun-
dation and the National Institutes of Health, General Medical
Sciences Institute (GM33049), for their generous support of
our programs. Mass spectra were provided by the Mass
Spectrometry Facility of the University of California-San
Francisco, supported by NIH Division of Research Re-
sources. We thank Johnson Matthey for their generous
donation of palladium salts.
Figure 3. Model for observed selectivity.
catalyst environment,22 the ionization event occurs prefer-
entially under the flap. For prenyl ester 5, this initially places
the prenyl group such that the primary carbon is under the
flap. In that conformation, nucleophilic addition also occurs
under the flap, leading to the results observed. The unfavor-
Supporting Information Available: Experimental details
for the synthesis of all intermediates, and characterization
data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(
21) The structure of the nucleophile generated by energy-minimized
Chem3D calculations.
22) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545-
554.
(
4
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Org. Lett., Vol. 9, No. 15, 2007