Enantioselective synthesis of the bromopyrrole alkaloids manzacidin A and C by stereospecific C-H bond oxidation

Article abstract of DOI:10.1021/ja028139s

The manzacidins represent a small family of structurally unique secondary metabolites found only sparingly in nature. Efforts to probe the pharmacological profile of these intriguing bromopyrrole alkaloids have been precluded by a deficiency of available

Full text of DOI:10.1021/ja028139s

Published on Web 10/12/2002
Enantioselective Synthesis of the Bromopyrrole Alkaloids Manzacidin A
and C by Stereospecific C-H Bond Oxidation
Paul M. Wehn and J. Du Bois*
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received August 14, 2002
Bromopyrrole alkaloids comprise a large and varied class of
marine natural products possessing interesting and potentially useful
pharmacological activities as R-adrenoreceptor blockers, seretonin
antagonists, and actomyosin ATPase activators.1 The manzacidins,
A, B, and C (1a-c), represent one small family of such compounds
isolated as bioactive constituents of the Okinawan sponge, Hyme-
niacidon sp (Figure 1).2,3 Subsequent evaluation of these metabolites
as possible therapeutic leads has been precluded by the lack of
available material from natural sources, thus motivating efforts to
prepare such structures through total synthesis.4 Our own interest
in formulating a route to the manzacidins is stimulated further by
the unusual chemical structures of these targets, which consist of
a uniquely substituted tetrahydropyrimidine core.5 Recently, we
have described a new method for saturated C-H bond function-
alization that makes possible the stereospecific installation of
tetrasubstituted carbinolamines.6 By employing this chemistry, a
rapid, enantioselective, and high throughput synthesis of both
manzacidins A and C has been achieved. In all, the demonstrated
work highlights the distinct power of C-H amination methodology
for simplifying problems in alkaloid synthesis.
Figure 2. Sulfamate ester insertion to install the tetrasubstituted C6
stereocenter.
Table 1. Selected Hydrogenation Reactions of Alcohol 5
entry
catalysta
ligand
6a/6cb
1
2
3
4
5
6
7
5% Pt-C
(Ph3P)3RhCl
Ir[(cod)(pyr)(PCy3)]PF6
Rh(cod)2OTf
Rh(nbd)2BF4
Rh(nbd)2BF4
Rh[((S,S)-Et-
DUPHOS)(cod)]OTf
none
none
none
50:50
50:50
65:35
75:25
40:60
20:80
>5:95
(R)-PHANEPHOSc
dppb
(R)-BINAP
none
a With the exception of entry 1, which was performed in C6H6 at 1 atm
H2, all other reactions were conducted in CH2Cl2 at ca. 1000 psi H2 (yields
are essentially quantitative). b Product ratio determined by 1H NMR
integration of the unpurified reaction mixture. c PHANEPHOS ) 4,12-
bis(diphenylphosphino)-[2.2]-paracyclophane.
Figure 1. Bromopyrrole alkaloids from Hymeniacidon sp.
explored using catalytic (Ph3P)3RhCl at varying H2 pressures (Table
1).8b All conditions tested, however, afforded a stereorandom
mixture of 6a and 6c.10 Fortunately, the application of chiral
phosphine ligands in combination with cationic Rh(I) sources and
5 provided a favorable solution to this problem.8a,10 As highlighted
in Table 1, either epimeric product may be prepared with good
selectivity depending on the choice of chiral catalyst.11 Following
sulfamoylation of the hydrogenated products 6a/6c (see Scheme
1), the individual diastereomers can be isolated as stereopure
materials.12 As observed first with sulfamate 7a, oxidative cycliza-
tion proceeds smoothly and stereospecifically with 2 mol % Rh2-
(OAc)4 and 1.1 equiv of PhI(OAc)2 to generate the crystalline
oxathiazinane product 8a in 85% yield. The combined four-step
process to 8a commencing from ethyl glyoxylate enables synthesis
of >5 g of the oxathiazinane in a single throughput.
Reaction of oxathiazinane 8a with Boc2O and pyridine is
performed as a first step toward completion of the manzacidin A
synthesis (Scheme 1). The unpurified carbamate 9a is treated
directly with NaN3 (DMF, 25 °C) to give the ring-opened product
(92%, two steps). Sequential reduction of the azido moiety in 10a
and acylation of the resulting amine occur in one operation and
generate formamide 11a quantitatively.13 A significant obstacle was
encountered, however, with the subsequent cyclodehydration of the
Oxidative C-H insertion of sulfamate esters under Rh catalysis
occurs efficiently and with absolute retention of configuration at
stereodefined tertiary centers (Figure 2).6a The product oxathiazinane
heterocycles 4 can be activated for facile nucleophilic ring opening
to give myriad 1,3-difunctionalized amine products.6a,7 Application
of this reaction sequence toward the synthesis of manzacidin A
thus leads to the identification of sulfamate ester 3 as a viable
precursor to the natural product. In principle, sulfamate 3 and its
C6 epimer (manzacidin numbering) could be fashioned from a
common synthetic intermediate, thereby facilitating a synthesis of
both manzacidins A and C through this stereospecific C-H insertion
strategy. Accordingly, homoallyl alcohol 2 was considered an
optimal starting material for our synthesis, as selective hydrogena-
tion of the prochiral alkene could afford either of the desired C6-
methyl diastereomers.8
Homoallyl alcohol 5 is readily available from ethyl glyoxylate
on a preparative scale (20 g) and in >90% ee through application
of an extremely efficient Evans’ asymmetric ene reaction.9 With
access to this compound, directed olefin hydrogenation was first
* To whom correspondence should be addressed. E-mail: jdubois@
stanford.edu.
9
12950
J. AM. CHEM. SOC. 2002, 124, 12950-12951
10.1021/ja028139s CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1a
encountered with the generation of optically pure tetrasubstituted
carbinolamines are conveniently addressed through the application
of stereospecific C-H amination methods developed by our lab,
and, as such, synthetic analysis of the manzacidins is greatly
simplified. In addition to highlighting this unique oxidation
chemistry, the path to these natural products showcases the
application of modern asymmetric methods for carbonyl-ene and
directed hydrogenation reactions, and the delineation of a novel
experimental protocol for tetrahydropyrimidine synthesis. The facile
preparation of hundreds of milligrams of these scarce natural
products offers testament to the power of these combined meth-
odologies.
a Conditions: (a) ClSO2NCO, HCO2H, 87% (3:1 mixture of C6 epimers);
(b) 2 mol % Rh2(OAc)4, PhI(OAc)2, MgO, CH2Cl2, 85%; (c) Boc2O, C5H5N;
(d) NaN3, DMF, 92%, two steps; (e) H2, Pd-C, then N-formylbenzotriazole;
(f) POCl3, 2,6-tBu2-4-MeC5H2N, 73%, two steps; (g) 8 M HCl, DME, 60
°C, NaHCO3, 60 °C, 99%.
Acknowledgment. P.M.W. gratefully acknowledges Eli Lilly
& Co. for graduate fellowship support. We thank Professor Paul
Wender and Mr. Christopher VanDeusen for use of and assistance
with preparative HPLC instrumentation. This work has been
supported by generous gifts from Merck and Pfizer, and by an award
from the Beckman Foundation.
C6 Boc-amine onto the C4 formyl unit. This problem was
exacerbated by the fact that little precedent exists for the assembly
of stereochemically complex tetrahydropyrimidine ring systems and
by our desire to formulate a protocol that would leave in place the
Boc-protecting group so as to facilitate purification of the highly
polar heterocycle.14 A screen of several dehydrating agents revealed
neat POCl3 with 0.75 equiv of 2,6-di-tert-butyl-4-methylpyridine
as an optimal solution.15 Under these conditions, the tetrahydro-
pyrimidine 12a is produced with the Boc group intact and without
attendant epimerization at C4 (73% from 10a). This compound may
be easily purified by chromatography on silica gel prior to
performing the final deprotection and bromopyrrole acylation steps.
Supporting Information Available: Experimental details and
analytical data for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
References
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Cleavage of the Boc, silyl ether, and ester groups in 12a is most
easily accomplished with 8 M HCl (DME, 60 °C). These conditions,
although somewhat forcing, provide the core structure of 1a in near
quantitative yield. Following the precedent of Ohfune, the resultant
acid-alcohol 13a reacts with excess NaH and 4-bromotrichloro-
acetylpyrrole to afford manzacidin A as a white solid (90% from
12a, eq 1), a compound identical in all respects to the natural
product (1H and 13C NMR, IR, HRMS, [R]D).4,16 Altogether, the
synthetic route to 1a comprises 10 linear steps from ethyl glyoxylate
with an overall yield of 28% and has enabled the preparation of
>350 mg of the desired target in a single pass. Through an identical
strategy beginning with sulfamate 6c, an equivalent amount of
manzacidin C has been prepared (32% overall, eq 2).17
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6005-6008.
(11) The catalyst prepared from Rh(cod)2OTf and (R,R)-Et-DUPHOS reverses
product selectivity, but gives only a 60:40 mixture of 6a/6c.
(12) In practice, we have found that separation is more easily accomplished
following sulfamate ester insertion.
(13) Katritzky, A. R.; Chang, H.-X.; Yang, B. Synthesis 1995, 503-505.
(14) (a) Girreser, U.; Heber, D.; Schu¨tt, M. Synthesis 1999, 1637-1641. (b)
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(16) Synthetic 1a: [R]27D ) -26.5° (c ) 0.65, MeOH). Natural 1a: [R]27
-28° (c ) 0.67, MeOH).
)
D
(17) In agreement with Ohfune’s findings (ref 4), the optical rotation of 1c
([R]27 ) +98° (c ) 0.76, MeOH)) differs substantially from the value
reportDed for the isolated natural product ([R]27 ) +37° (c ) 0.23,
MeOH)). This discrepancy may be attributed to iDmpurities in natural 1c.
The synthesis of manzacidins A and C demonstrates for the first
time the efficacy of Rh-catalyzed sulfamate ester insertion reactions
in the context of complex natural product synthesis. Problems
JA028139S
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J. AM. CHEM. SOC. VOL. 124, NO. 44, 2002 12951