Toward the total synthesis of the brasilinolides: Construction of a differentially protected C20-C38 segment

Article abstract of DOI:10.1021/ol802769e

(Chemical Equation Presented) An efficient, convergent synthesis of a differentially protected C20-C38 segment of the brasilinolides is described. Iterative 1,4-syn aldol additions and ketone reductions were employed to construct the two related stereotet

Full text of DOI:10.1021/ol802769e

ORGANIC
LETTERS
2009
Vol. 11, No. 3
693-696
Toward the Total Synthesis of the
Brasilinolides: Construction of a
Differentially Protected C20-C38
Segment
Ian Paterson,*,† Paul M. Burton,† Christopher J. Cordier,† Michael P. Housden,†
Friedrich A. Mu¨hlthau,† and Olivier Loiseleur‡
UniVersity Chemical Laboratory, Lensfield Road, Cambridge, CB2 1EW, U.K., and
Syngenta Crop Protection AG, Schaffhauserstrasse, 4332 Stein, Switzerland
ip100@cam.ac.uk
Received December 1, 2008
ABSTRACT
An efficient, convergent synthesis of a differentially protected C20-C38 segment of the brasilinolides is described. Iterative 1,4-syn aldol
additions and ketone reductions were employed to construct the two related stereotetrads, while a sequence of Horner-Wadsworth-Emmons
(HWE) coupling, CBS reduction, and Sharpless AE installed the epoxy alcohol functionality.
Following on from the spectacular clinical success of the
cyclosporins in counteracting tissue rejection in human organ
transplantation, the brasilinolides (1a-c, Scheme 1) are a
recent addition to an important class of immunosuppressive
macrolides that include FK506, rapamycin, and sanglifehrin.1
First isolated in 1996 by the Mikami and Kobayashi groups
from the pathogenic actinomycete Nocardia brasiliensis
IFM-0406,2 brasilinolide A (1a) exhibited immunosuppres-
sive activity in the mouse mixed lymphocyte reaction, with
an IC50 of 0.625 µg/mL, and showed no toxicity at 500 mg/
kg. The congeneric macrolide brasilinolide B (1b) was
reported to be active against a range of fungi and bacteria.3
Recently, the relative and absolute configuration was deter-
mined inter alia by controlled chemical degradation of a third
congener, brasilinolide C (1c), and detailed spectroscopic
studies of the resulting fragments.4
Altogether, the pronounced biological activities of the
brasilinolides, along with the low toxicity profile and
favorable physicochemical properties, make their further
evaluation as lead structures appealing. Following on from
our recently reported synthesis of the southern C1-C19
polyol segment 2 of the brasilinolides,5 we now describe an
efficient stereocontrolled construction of the corresponding
differentially protected C20-C38 northern hemisphere 3.
As outlined in Scheme 1, access to all three congeners of
the brasilinolides was planned to arise from the late-stage
attachment of the appropriate C23 side chain and C37-O-
† University of Cambridge.
‡ Syngenta.
(1) For a review of natural products as immunosupressive agents, see:
Mann, J. Nat. Prod. Rep. 2001, 18, 417.
(2) (a) Shigemori, H.; Tanaka, Y.; Yazawa, K.; Mikami, Y.; Kobayashi,
J. Tetrahedron 1996, 52, 9031. (b) Tanaka, Y.; Komaki, H.; Yazawa, K.;
Mikami, Y.; Nemoto, A.; Tojyo, T.; Kadowaki, K.; Shigemori, H.;
Kobayashi, J. J. Antibiot. 1997, 50, 1036.
(3) Mikami, Y.; Komaki, H.; Imai, T.; Yazawa, K.; Nemoto, A.; Tanaka,
Y.; Gra¨fe, U. J. Antibiot. 2000, 53, 70.
(4) Komatsu, K.; Tsuda, M.; Tanaka, Y.; Mikami, Y.; Kobayashi, J. J.
Org. Chem. 2004, 69, 1535.
(5) Paterson, I.; Mu¨hlthau, F. A.; Cordier, C. J.; Housden, M. P.; Burton,
P. M.; Loiseleur, O. Org. Lett. 2009, 11, 353–356.
10.1021/ol802769e CCC: $40.75
Published on Web 01/05/2009
2009 American Chemical Society

Scheme 1. Retrosynthetic Analysis of the Brasilinolides
glycosidation, following closure of the 32-membered mac-
rolide. The northern portion of the brasilinolide structure is
characterized by 11 contiguous stereocenters, together with
an isolated stereocenter at C23, and requires suitable dif-
ferentiation of six secondary hydroxyls in the synthetic route,
as well as installation of the epoxide. A complex aldol
coupling between methyl ketone 3 and a C19 aldehyde
derived from 2 was proposed, followed by C21 reduction
and hemiacetal formation, leading to the projected assembly
of the full C1-C38 seco-acid precursor. Further analysis of
segment 3 suggested a C28-C29 disconnection as an
attractive way to handle the installation of the epoxide and
the remote C23 stereocenter, leading back, in turn, to
phosphonate 4 and the stereochemically elaborate aldehyde
5. As indicated in Figure 1, detailed examination of aldehyde
5 reveals two similar stereotetrads with an epimeric relation-
ship between C31 and C35. Thus, two iterative aldol
reactions employing the (E)-dicyclohexylboron enolates
derived from the ethyl ketones 6 and 7 (Scheme 1) were
selected to configure the contiguous 1,4-syn-3,4-anti relation-
ships Via effective substrate-based induction.6 Consequently,
aldol-type bond scissions across C32-C33 and C36-C37
in 5 were envisaged, with the C31 and C35 hydroxyl centers
to be installed Via appropriate ketone reductions.
Scheme 2
Synthesis of the initial stereotetrad associated with the
C33-C38 aldehyde 8 (Scheme 2) commenced with enoliza-
tion of the ethyl ketone 76a using c-Hex2BCl/Et3N. Addition
(6) (a) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig,
N. J. Am. Chem. Soc. 2001, 123, 9535. (b) Paterson, I.; Norcross, R. D.;
Ward, R. A.; Romea, P.; Lister, M. A. J. Am. Chem. Soc. 1994, 116, 11287.
(c) Paterson, I.; Ashton, K.; Britton, R.; Cecere, G.; Chouraqui, G.; Florence,
G. J.; Knust, H.; Stafford, J. Chem. Asian J. 2008, 3, 367.
Figure 1. Stereotetrads embedded in the C29-C38 segment.
694
Org. Lett., Vol. 11, No. 3, 2009

Scheme 3
Scheme 4
of the resulting (E)-enolate to acetaldehyde set the 1,4-syn-
3,4-anti relationship in the intermediate aldolate 9 as
expected6 and was followed by an in situ ketone reduction
using LiBH4.7 After oxidative cleavage of the resulting
boronate ester, the 1,3-syn diol 10 was isolated in 88% yield
and >95:5 dr, thereby efficiently controlling the configuration
at the three new stereocenters. The hydroxyl groups were
then differentiated8a by exposure of the PMB ether 10 to
anhydrous DDQ oxidation conditions which afforded the
corresponding six-membered PMP acetal in 92% yield. A
DEIPS group8b was then appended to the remaining C37
hydroxyl to give the ether 11 (97%). Further elaboration to
the aldehyde 8 was then effected by the regioselective
reductive ring opening of the PMP acetal using DIBAL and
Dess-Martin periodinane-mediated oxidation of the resulting
C33 alcohol.
With aldehyde 8 in hand, attention focused on the
installation of the second stereotetrad contained within the
C30-C38 tetrapropionate segment of the brasilinolides
(Scheme 3). Thus, an aldol addition of the (E)-dicyclohexy-
lboron enolate derived from ethyl ketone 66b to aldehyde 8
was initiated at -78 °C and, with warming to -20 °C in
Et2O, afforded adduct 12 cleanly (87%, >95:5 dr). On this
occasion, a 1,3-anti reduction9 of the aldol adduct was
required. Consequently, treatment of 12 with
Me4NBH(OAc)3 gave the corresponding 1,3-anti diol with
high diastereoselectivity. Once again, we were able to
differentiate the hydroxyl groups formed in this operation
by using DDQ to oxidize the PMB ether at C35 and generate
the PMP acetal 13 in 85% yield.10 The remaining strategi-
cally important alcohol at C31 was then protected as a TES
ether. Care was needed to chemoselectively cleave the C29
benzyl ether in the presence of the PMP acetal. Yonemitsu
and co-workers’ hydrogenolysis conditions using W-2 Raney
nickel proved to be optimum (92%),11 giving the desired
primary alcohol with no detectable PMP acetal cleavage.
Finally, a Dess-Martin oxidation provided the required
C29-C38 aldehyde 5 in 11 steps and 32% overall yield from
ketone 7. This efficient aldol-based sequence proved readily
scalable and was used to produce multigram quantities of 5.
Attention now turned to the preparation of the ꢀ-keto-
phosphonate 4 required as the HWE coupling partner for 5
(Scheme 4). After some experimentation, a hydrolytic kinetic
resolution (HKR) approach was selected to set the config-
uration at C23. Thus, alkene 14 was epoxidized using
mCPBA and then subjected to the HKR conditions developed
by Jacobsen and co-workers,12 using (R,R)-Co(salen) as the
catalyst, to provide essentially enantiopure 15. This epoxide
in turn was opened by isopropenyl magnesium bromide in
the presence of catalytic CuI to give alcohol 16 (99% ee).
Next, DMB protection of 16 (NaH, DMBCl) was followed
by cleavage of the TBS ether in 17 to give the alcohol 18.
Conversion of the derived aldehyde 19 into the ꢀ-ketophos-
phonate
4
was accomplished by addition of
LiCH2P(O)(OMe)2 and subsequent Dess-Martin periodinane-
mediated oxidation. This readily scalable sequence proceeded
in 19% overall yield from 5-hexen-1-ol.
With both fragments 4 and 5 in hand, we could now
investigate their Horner-Wadsworth-Emmons coupling
(Scheme 5). A screen of HWE conditions revealed Ba(OH)2
in wet THF13 to be optimum, affording the enone 20 cleanly
(91%, >95:5 E:Z). Importantly, this reaction proceeded
(7) Paterson, I.; Perkins, M. V. Tetrahedron 1996, 52, 1811.
(8) (a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 889. (b) The selection of hydroxyl protecting groups in the C20-C38
segment 3 was made to potentially enable access to all three brasilinolide
congeners by suitable derivatization at C23 and C37.
(11) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021.
(9) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560.
(12) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen,
K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc.
2002, 124 (7), 1307.
(10) The (33R, 34S, 35R) configurational assignments were confirmed
by NOE analysis of this acetal (see the Supporting Information).
(13) Paterson, I.; Yeung, K-S.; Smaill, J. B. Synlett 1993, 774.
Org. Lett., Vol. 11, No. 3, 2009
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installed using Sharpless asymmetric epoxidation conditions
employing (+)-DIPT/Ti(iOPr)4/tBuOOH (59%, 7:1 dr).16
Following TBS protection of the C27 hydroxyl in 22, the
required ketone at C21 was introduced Via OsO4-mediated
dihydroxylation of the alkene and cleavage of the resulting
diol with NaIO4/SiO217 to afford 3 (86%), corresponding to
the targeted C20-C38 segment of the brasilinolides.
In summary, we have developed a highly stereocontrolled
synthesis of a differentially protected C20-C38 segment 3
of the brasilinolides that proceeds in 16 steps and 13% overall
yield in the longest linear sequence from the ethyl ketone
(S)-7.18 Studies into the complex aldol coupling of methyl
ketone 3 with a suitable C19 aldehyde derived from 25
(Scheme 1), together with further efforts toward completion
of the total synthesis of the brasilinolide macrolides, are
ongoing.
Scheme 5
Acknowledgment. We thank the EPSRC (EP/F025734/
1) and Syngenta for support and the Deutsche Akademie der
Naturforser Leopoldina (F.A.M.; BMBF-LPD 9901/8-148)
and the Herchel Smith Postdoctoral Fellowships Fund at
Cambridge (C.J.C.) for additional funding.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL802769E
(14) The (27S)-configuration was confirmed by Mosher ester analysis
using the Kakisawa method (see the Supporting Information). Ohtani, I.;
Kasumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
4092.
without any detectable elimination of the C31-OTES group
from aldehyde 5, which proved to be a persistent problem
when using other bases.
A reagent-controlled reduction of enone 20 was now
required. The (R)-Me-CBS reagent was found to give
excellent selectivity in setting the desired configuration at
C27, leading to the allylic alcohol 21 (88%, >95:5 dr).14,15
The correctly configured trans-epoxide in 22 was then
(15) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K.
J. Am. Chem. Soc. 1987, 109, 7925.
(16) (a) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765. (b) Johnson, R. A.;
Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH
Publishers: New York, 1993; p 103.
(17) Zhong, Y.-L.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622.
(18) This is prepared in three steps and 77% yield from methyl (S)-2-
methyl-3-hydroxypropionate (see ref 6a).
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Org. Lett., Vol. 11, No. 3, 2009