Exploring symmetry-based logic for a synthesis of Palau'amine

Article abstract of DOI:10.1021/jo900755r

(Chemical Equation Presented) A synthetic approach to palau'amine is described that exploits veiled symmetry in the structure. Bis-alkylidenes i have been prepared and found susceptible to halogenative desymmetrization using t-BuOCl. This oxidation forms

Full text of DOI:10.1021/jo900755r

pubs.acs.org/joc
Exploring Symmetry-Based Logic for a Synthesis of Palau’amine
Qingyi Li,‡,§ Paul Hurley,‡,†, Hui Ding,† Andrew G. Roberts,† Radha Akella,‡ and
Patrick G. Harran*,†
†Department of Chemistry and Biochemistry, University of California, 607 Charles E. Young Drive East,
Los Angeles, California 90095-1569, and ‡Department of Biochemistry, University of Texas Southwestern
Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038. Current address: Cubist
§
Pharmaceuticals, Inc., 65 Hayden Ave, Lexington, MA 02421. Current address: Gilead Alberta ULC, 1021
Hayter Rd, Edmonton, AB T6S 1A1, Canada
harran@chem.ucla.edu
Received April 23, 2009
A synthetic approach to palau’amine is described that exploits veiled symmetry in the structure.
Bis-alkylidenes i have been prepared and found susceptible to halogenative desymmetrization using
t-BuOCl. This oxidation forms the imbedded spirocyclopentane motif observed in the natural
product. A host of atypical reactions and processes developed during these studies are discussed, as
are plans for completing total syntheses of this compound class.
Introduction
insightful work on autoxidative incorporation of guanidine
into partially oxidized proline dimers.5 This direct access to
displacamides from a non oroidin source adds another dimen-
sion to biosynthesis considerations.
Palau’amine (1, Figure 1)1 is a prominent member of the
pyrrole/imidazole family of marine derived alkaloids, a group
whose numbers continue to grow with research on selected
pacific sponges. Relationships within the group have been
discussed extensively, relating mainly to proposals for unified
biosynthetic schemes.1b,2 While direct evidence is lacking, an
early consensus viewed the class as originating with 3-amino-
1-(2-aminoimidazolyl)prop-1-ene (2).3 One can trace this
motif in scores of natural products described throughout four
decades of literature. In this scenario, aminoimidazole 2 and
pyrrole-2-carboxylic acid are constituents of oroidin,4 itself
the feedstock from which the larger family derives;perhaps
wherein genes encoding enzymatic machinery manipulating
intermediates have transferred and evolved across producing
species.2a An alternate view stems from Al-Mourabit’s recent
Origins notwithstanding, palau’amine and its relatives
harbor two units of aminoimidazole 2. It is these dimeric
conjugates that make up the most structurally and biochemi-
cally interesting members of the set. Palau’amine was iso-
lated as an antifungal constituent of S. aurantium.1 The
substance was also reported to possess antimicrobial activity
and to inhibit stimulated human T-cell proliferation in vitro,
while being relatively innocuous to resting lymphocytes.
To date these functions have not been examined further or
characterized at a molecular level. Actually, the same is true
of the various biological effects attributed to other palau’a-
mine type bis-guanidines. The stalemate derives from a
scarcity of the materials in nature and the fact that assem-
bling related structures in the laboratory has proven an
unusually difficult problem.
(1) (a) Kinnel, R. B.; Gehrken, H.-P.; Scheuer, P. J. J. Am. Chem. Soc.
1993, 115, 3376–3377. (b) Kinnel, R. B.; Gehrken, H.-P.; Swali, R.;
Skoropowski, G.; Scheuer, P. J. J. Org. Chem. 1998, 63, 3281–3286.
(2) (a) Al-Mourabit, P., Potier Eur. J. Org. Chem. 2001, 237–243. (b)
Baran, P. S.; O’Malley, D. P.; Zografos, A. L. Angew. Chem., Int. Ed. 2004,
The imbedded cyclopentane scaffolding the two guanidine
units within 1 is its signature feature. Installing this motif
€
43, 2674–2677. (c) Grube, A.; Immel, S.; Baran, P. S.; Kock, M. Angew.
Chem., Int. Ed. 2007, 46, 6721–6724.
(3) Wright, A. E.; Chiles, S. A.; Cross, S. S. J. Nat. Prod. 1991, 54, 1684–
1686.
(4) (a) Garcia, E. E.; Benjamin, L. E.; Fryer, R. I. J. Chem. Soc., Chem.
Commun. 1973, 78–79. (b) Gautschi, J. T.; Whitman, S.; Holman, T. R.;
Crews, P. J. Nat. Prd. 2004, 67, 1256–1261.
(5) (a) Ravert, N.; Al-Mourabit, A. J. Am. Chem. Soc. 2004, 126, 10252–
10253. (b) Vergne, C.; Boury-Esnault, N.; Perez, T.; Martin, M.-T.; Adeline,
M.-T.; Dau, E. T. H.; Al-Mourabit, A. Org. Lett. 2006, 8, 2421–2424. (c)
Vergne, C.; Appenzeller, J.; Ratinaud, C.; Martin, M.-T.; Debitus, C.;
Zaparucha, A.; Al-Mourabit, A. Org. Lett. 2008, 10, 493–496.
DOI: 10.1021/jo900755r
r
Published on Web 07/16/2009
J. Org. Chem. 2009, 74, 5909–5919 5909
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Li et al.
JOCArticle
oxidation. We describe here methods to synthesize the requi-
site monomers and show their dimerization can be uniquely
executed in both a regio- and stereocontrolled manner.
We further demonstrate that derived bis-alkylidenes 3 are
in fact susceptible to halogenative spirocyclization, validating
our blueprint for syntheses of palau’amine type alkaloids
generally.
Results and Discussion
The ring system in 6 had not been synthesized previously,
although a generic relationship to simpler components was appar-
ent (Figure 1). The Claisen condensation product of γ-butyro-
lactone and (CO2Et)2 was degraded with HBr/AcOH and the
crude reaction treated with MeOH/cat. H2SO4 to afford bromi-
nated R-keto ester 7 (Scheme 1).10 This material was exposed to
hydrazine to generate a tetrahydropyridazine carboxylate11
that was subsequently allylated and saponified to afford 8.
When carboxylic acid 8 was condensed with o-xylyldiamine-
derived methylisothiourea 9,12 the adduct (10) could be induced
to cyclize in situ by concentrating the reaction mixture at 70 °C
in vacuo. This served to generate the desired N-aminoglyco-
cyamidine 11 via net extrusion of methyl mercaptan.
With 11 in hand, we set out to dimerize the material using
enolate oxidation techniques.13 Enamide 11 could be deproto-
nated readily at low temperature with KHMDS. The resultant
dienolate was prone to oxygenation,14 but if anaerobic con-
FIGURE 1. Original and revised palau’amine structures. In either
case, the imbedded spirocyclopentane motif can be viewed as a
product of halogenative desymmetrization.
15
ditions were established, addition of FeCl2(DMF)3FeCl4
generated dimeric products efficiently. With the original
assignment of palau’amine stereochemistry1,16 (namely, 1a)
becomes de facto the central event in any projected synthesis.
Several laboratories have published creative models on
the topic and tactics range from putatively biomimetic to
decidedly abiotic.6 Overman’s beautiful work in the area has
reached an advanced stage.7 Baran et al. have recently
reported the first synthesis of axinellamines and massa-
dines;truly seminal achievements.8a,8b Our own experi-
ments fall in the biomimetic vein wherein we view the
carbocycle in 1 as derivative of oxidative halogenation; in
particular of seco-bis-alkylidenes 3.9 This choice makes sym-
metry in the problem clear, provides options for varying
diastereochemical outcomes and, assuming 4 to be a viable
intermediate en route to 1, reduces the initial task to that of
controllably dimerizing a dispacamide alkaloid.5b We targeted
fused heterobicycle 6 as a dispacamide synthon for this pur-
pose, such that dimerization could occur via a derived dienolate
(10) Ohler, E.; Schmidt, U. Chem. Ber. 1975, 2907–2916.
(11) Broger, E. M.; Crameri, Y.; Imfeld, M.; Montavon, F.; Widmer, R.
Eur. Pat. Appl. 1993, EP 570764.
(12) (a) Kawahara, S.; Uchimaru, T. Z. Naturforsch., B: Chem Sci. 2000,
55, 985–987. (b) Elslager, E. F.; Worth, D. F.; Haley, N. F.; Perricone, S. C. J.
Heterocycl. Chem. 1968, 5, 609–612.
€
(13) (a) Kauffmann, T.; Neissner, G.; Koppelmann, B. E.; Legler, J.;
Schonfelder, M. Angew. Chem., Int. Ed. 1968, 7, 540–541. (b) Ito, Y.;
€
Konoike, T.; Harada, T.; Seagusa, T. J. Am. Chem. Soc. 1977, 99, 1487–
1493. (c) Renaud, P.; Fox, M. A. J. Org. Chem. 1988, 53, 3745–3752. (d)
Porter, N. A.; Su, Q.; Harp, J. J.; Rosenstein, I. J.; MaPhail, A. T.
Tetrahedron Lett. 1993, 34, 4457–4460. (e) Schmittel, M. Top. Curr. Chem.
1994, 183–230. (f) Richter, J. M.; Whitefield, B. W.; Maimone, T. J.; Lin, D.
W.; Castroviejo, M. P.; Baran, P. S. J. Am. Chem. Soc. 2007, 129, 12857–
12869.
(14) The yield of dimeric products in nondeoxygenated solvents is
lowered due to competing formation of angularly hydroxylated monomer
45. Compound 45 also forms (75% yield) when 11 is treated with KHMDS
alone (1.1 equiv, -78 °C, 0.2M, 1 h) in nondeoxygenated THF. Compound
45 presumably derives from a corresponding hydroperoxide which is either
reduced in situ or hydrolyzed during isolation.
€
(6) For reviews, see: (a) Kock, M.; Grube, A.; Seiple, I. B.; Baran, P. S.
Angew. Chem., Int. Ed. 2007, 46, 6586–6594. (b) Jacquot, D. E. N.; Lindel, T.
Curr. Org. Chem. 2005, 9, 1551–1565. For recent contributions, see: (c)
Namba, K.; Kaihara, Y.; Imagawa, I.; Tanino, K.; Williams, R. M.; Nishizawa, M.
Chem.;Eur. J. 2009, 15, 6560–6563. (d) Hudon, J.; Cernak, T. A.; Ashenhurst,
J. A.; Gleason, J. L. Angew. Chem., Int. Ed. 2008, 47, 8885–8888. (e) Cernak, T.
A.; Gleason, J. L. J. Org. Chem. 2008, 73, 102–110. (f) Bultman, M. S.; Ma, J.;
Gin, D. Y. Angew. Chem., Int. Ed. 2008, 47, 6821–6824. (g) Zancanella, M. A.;
Romo, D. Org. Lett. 2008, 10, 3685–3688. (h) Wang, S.; Romo, D. Angew.
Chem., Int. Ed. 2008, 47, 1284–1286. (i) Sivappa, R.; Hernandez, N. M.; He, Y.;
Lovely, C. J. Org. Lett. 2007, 9, 3861–3864. (j) Spoering, R. M. Studies Toward a
Synthesis of Palau'amine. Ph.D Thesis, Harvard University, 2005.
(7) Lanman, B. A.; Overman, L. E.; Paulini, R.; White, N. S. J. Am.
Chem. Soc. 2007, 129, 12896–12900 and references cited therein .
(8) (a) O’Malley, D. P.; Yamaguchi, J.; Young, I. S.; Seiple, I. B.; Baran,
P. S. Angew. Chem., Int. Ed. 2008, 47, 3581–3583. (b) Su, S.; Seiple, I. B.;
Young, I. S.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 16490–16491.
(9) Garrido-Hernandez, H.; Nakadai, M.; Vimolratana, M.; Li, Q.;
Doundoulakis, T.; Harran, P. G. Angew. Chem., Int. Ed. 2005, 117, 765–
769.
(15) Tobinaga, S.; Kotani, E. J. Am. Chem. Soc. 1972, 94, 309–310.
(16) Recent evidence suggests Scheuer and Kinnel’s assignment of pa-
lau’amine relative stereochemistry (ref 1) is likely incorrect. Characterization
of newly isolated relatives implies natural palau’amine is configured as drawn
in 1b. For details, see: (a) Kobayashi, H.; Kitamura, K.; Nagai, K.; Nakao,
Y.; Fusetani, N.; van Soest, R. W. M.; Matsunaga, S. Tetrahedron Lett. 2007,
48, 2127–2129. (b) Buchanan, M. S.; Carroll, A. R.; Addepalli, R.; Avery, V.
M.; Hooper, J. N. A.; Quinn, R. J. J. Org. Chem. 2007, 72, 2309–2317. (c)
€
Grube, A.; Kock, M. Angew. Chem., Int. Ed. 2007, 46, 2320–2324. Over-
man’s (ref 7) and Baran’s (ref 8) synthetic studies further support these
arguments.
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SCHEME 1a
It therefore seemed reasonable to infer the Fe(III)-
based procedure (entry 1) involved an organometallic
species whose homocoupling was more responsive to
ground-state stability of incipient products. If true,
furthering that trend could make the γ,γ outcome compe-
titive, perhaps favored, provided regioisomers 14 were
indeed lower in relative energy.23 Replacing Fe(III) with
Cu(II) did increase the proportion of 14 formed (entry 3),
although the reaction remained impractical for pre-
parative purposes. The breakthrough came when the po-
tassium dienolate was treated with an equivalent of
Cp2TiCl2 prior to oxidation. In that case, we obtained
largely desired regioisomers 14 in good yield (Scheme 3).
When (i-PrCp)2TiCl2 was used, selectivity for 14 was
essentially complete; regioisomers 12 or 13 could no longer
be detected in crude reaction mixtures. Our understanding
of the mechanism operating is limited. However, reasoning
by analogy to Schmittel’s findings on the electro-
chemical oxidation of simpler titanocene enolates,24 we
interpret the outcome in terms of Cu(II) engaging an
intermediate of type 15 to initiate dimerization via an
electron-deficient species whose Ti-O bond is intact at
the point of C-C bond formation.25 This would effectively
block the dienolate R position. Attempts to further char-
acterize details of this atypical oxidative coupling are
ongoing.
Our initial plans for palau’amine synthesis called for
removing one allyl unit from meso-14 en route to a substance
carrying the acylpyrrole unit on N2 (see Figure 1) needed to
construct the dipyrrolopyrazinone motif found in 1 (vide
infra). Unfortunately, the seemingly simple task of deal-
lylating 14a/b proved untenable, at least by direct means.26
Thus, a more ambitious goal was pursued wherein the
acylpyrrole component would be installed early and carried
through the synthesis, giving our dimeric intermediates the
bis-pyrrole composition common to axinellamine, massa-
dine, carteramine, and konbu’acidin.6,16 The monomer
aReaction conditions: (a) 1 equiv of NH2NH2,10 equiv of AcOH, MeOH/H2O,
rt to 62 °C (>95%); (b) 1 equiv of KHMDS; 1.2 equiv of allyl bromide, THF,
-35 °C (90%); (c) 1.5 equiv of LiOH, 2:1:1 THF/MeOH/H2O; aq citric acid
(>95%); (d) 1.1 equiv of 9, 1 equiv of TBTU, 3 equiv of (i-Pr)2NEt, DMF,
then concentrates in vacuo at 70 °C (72%). TBTU = 2-(1H-benzotriazol-1-yl)-
1,1,3,3-tetramethyluronium tetrafluoroborate.
in mind, the desired outcome was a meso dimer resulting
from homocoupling at the γ position of monomer 11
(namely 14a, Scheme 2). However, little of that material
was formed. Rather, we obtained predominately a diastereo-
meric mixture of R,γ adducts 12 along with lesser amounts of
R,R regioisomer 13.17 The trace amount of 14 observed was
present as a 1:1 mixture of meso and C2 forms.18 We subse-
quently found that R,R coupling product 13 was unstable and
rearranged to R,γ forms 12 in toluene solution at 85 °C.19
Rather than disproportionate or Cope rearrange to γ,γ iso-
mers 14, the molecule undergoes a net 1,3-sigmatropic shift. It
was possible to purify 13 and photolyze the compound to
generate additional 14, although this protocol was inefficient
and continued to afford substantial amounts of 12. This result,
and the fact we were unable to independently convert 12 to its
γ,γ counterparts 14,20 necessitated that attention turn to
controlling kinetic selectivity in the oxidative dimerization
itself.
We observed that substituting I2 for FeCl2(DMF)3FeCl4
as the oxidant (Scheme 2) provided for a similarly efficient
dimerization, although 14 was no longer detectable in the
crude reaction mixture and the ratio of dimeric products now
favored isomers 13. This was interpreted in terms of a mono-
meric radical dimerizing through an early, reactant-like tran-
sition state.13c,21 Independently, FeCl2(DMF)3FeCl4 was
found not to convert 13 into 14 in THF solution at rt.22
(23) This statement reflects a corollary to the Hammond postulate.
However, available data do not confirm kinetic control nor have we
determined that “homocoupling” is, in fact, mechanistically accurate.
The heterogeneous nature of the reactions complicates in situ observa-
tions. We speculate only to convey reasoning as our experiments pro-
gressed.
€
(24) (a) Schmittel, M.; Sollner, R. Chem. Ber. 1997, 771–777. (b) Schmittel,
M.; Burghart, A.; Malisch, W.; Reising, J.; Sollner, R. J. Org. Chem. 1998, 63,
€
396–400.
(25) This may not be the case in oxidations involving FeCl2(DMF)3FeCl4,
wherein significant amounts of R,γ-regioisomeric dimers are consistently
observed (Schemes 2 and 5).
(26) The hydrohexafluorophosphate salt of 11 could be deallylated using
the two-step sequence shown below. Unfortunately, these methods proved
neither an efficient nor selective means to deprotect 14.
(17) A single diasteromer of 12, the dl form of 13, 21-meso, polycycle 29,
and reduction products 33b have been characterized by X-ray crystallogra-
phy. See the Supporting Information for details.
(18) Meso and racemic C2 forms 14a/14b are inseparable by silica gel
chromatography. Ratios are determined by 1H NMR and HPLC analyses
(Chiralcel-OD-H, isocratic: 80% i-PrOH/hexanes).
(19) T1/2 for the conversion 13 f 12 in toluene solution at 85 °C is 56 min
(Ea ∼ 27 kcal/mol).
(20) Attempts to establish equilibrium between 12 and 14, which
would presumably favor 14 for steric reasons, failed. Such experiments
included thermolyses, acid (Lewis and Bronstead) treatments, and
exposure to catalysts intended to generate ion-paired metal π-allyl inter-
mediates.
(21) Ziegler, F. E.; Harran, P. G. J. Org. Chem. 1993, 58, 2768–2773.
(22) A 0.1 M THF solution of 13 is unchanged at room temperature after
2 h in the presence of 0.6 equiv of FeCl2(DMF)3FeCl4.
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Li et al.
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SCHEME 2a
aReaction conditions: (a) 1.05 equiv of KHMDS, degassed THF, -78 °C, 30 min; add 1.1 equiv of oxidant and stir for 1 h at -78 °C; (b) 0.02 M 13 in degassed
toluene, 95 °C, 1 h (81%); (c) hν (Rayonet, 254 nm bulb set), 0.01 M in deoxygenated PhH, 2 h (36% 12 + 20% 14a/b); (d) 12 isolated as ∼1:1 mixture of dias-
tereomers; (e) only dl form observed (ref 18); (f) 14 isolated as an equal mixture of meso amd racemic C2 forms.
SCHEME 3a
21 (3.3:1 meso/C2) in respectable yield (Scheme 5). Notably,
changing the oxidant to FeCl2(DMF)3FeCl4 reversed the
selectivity to now favor the C2 isomer (1:3 meso/C2). The yield
in this case was diminished due to competing formation of
R,γ regioisomeric dimers. Nonetheless, selectivity and efficiency
observed were encouraging given the complexity of the
construction.
With meso-21 assembled, we again faced a desymmetriza-
tion, yet one quite different than confronted in 14. Plans
called for saturating a single N-N σ bond en route to a
compound of type 24 (Scheme 6A). Models suggested reliev-
ing one such ring constraint would provide flexibility nece-
ssary for the intended spirocyclization (as drawn), while the
N-N bond remaining would enforce a syn relationship
between the C-Cl bond and C18 aminomethyl branch
within polycycle 25 generated upon chlorination. Of course,
this outcome would require chemoselective halogenation of
the vinyl hydrazide in 24, itself a tenuous proposal. However,
the alternative was to delay desymmetrization and break
aReaction conditions: (a) KHMDS (1.1 equiv), deoxygenated THF, -78 °C,
both N-N bonds in 21 en route to bis-alkylidenes of type
30 min; then (R-Cp)2TiCl2 (1.15 equiv), -78 °C, 3 h; then Cu(OTf)2
3 (Figure 1). The concern there was that stacked conformers
(1.6 equiv), -78 °C, 3.5 h; (b) 20% yield of 12 and 10% recovered 11 isolated
having minimal allylic strain in the tether connecting glyco-
in this experiment.
cyamidine units would react preferentially to give products
having a trans relationship between ring substituents at
required for this purpose was synthesized beginning with
tetrahydropyridazine 16 (Scheme 4). This material was
treated with acid chloride 1727 and the adduct saponified
to afford carboxylic acid 18. Condensation with methyli-
sothiourea 9 subsequently provided amide 19 from which
target 20 was derived by mild thermolysis in the presence of
HgCl2.28
(28) The use of substoichiometric amounts of HgCl2 in the reaction leads
to isolation of angular thioether 46. This material can be converted inde-
pendently to 20 by re-exposure to HgCl2/pyr (CH3CN, 70 °C).
The potassium dienolate of 20 decomposed readily at -78 °C.
However, if 20 was treated with (i-PrCp)2TiCl2 prior to
KHMDS, subsequent oxidation with Cu(OTf)2 afforded dimers
(27) Katz, J. D.; Overman, L. E. Tetrahedron 2004, 60, 9559–9568.
5912 J. Org. Chem. Vol. 74, No. 16, 2009

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SCHEME 4a
SCHEME 5a
aReaction conditions: (a) 0.95 equiv of 17, pyr, CH3CN, rt (94%); (b) LiOH,
1:1 THF/H2O, 0 °C (95%), recrystallized; (c) 1.05 equiv of 9, HI, 1.1 equiv
of TBTU, 3 equiv of (i-Pr)2NEt, DMF, rt (>95%); (d) 1.5 equiv of HgCl2, 3
equiv of pyr, CH3CN, reflux 3 h (70%).
aReaction conditions: (a) (i-PrCp)2TiCl2 (1.15 equiv), deoxygenated THF, 0
to -78 °C, 30 min; then KHMDS (1.1 equiv), -78 °C, 1.5 h; then Cu(OTf)2
(1.5 equiv) or FeCl2(DMF)3FeCl4 (1 equiv), 3 h, -78 °C to rt, 1.5 h; (b) 20%
yield of R,γ dimers (analogous to 12) are isolated in this experiment. meso-21
has been characterized by X-ray crystallography (ref 17).
carbons 17 and 18. This was unacceptable in light of
Scheuer’s original palau’amine assignment (1a) and, thus,
means to generate structures 24 took priority.
A two-electron reduction of 21 having the effect of satur-
ating one N-N bond was an interesting problem. We chose
to pursue a conjugate addition manifold, the thought being
hydride addition to one enamide could generate a transient
ketene aminal (e.g., 22) perhaps able to β-eliminate, wherein
the ring-opened product (23) would tautomerize upon pro-
tonation to give 24. In practice, working with meso-21,
procedures employing various soft metal hydrides, either
as isolated reagents or generated in situ, were ineffective for
this purpose. However, we did observe that Wilkinson’s
complex could catalyze partial reduction of 21 to afford
27 in the presence of PhMe2SiH,29 provided that 21 was
pretreated with 2 equiv of NH4PF6 to suppress catalyst
poisoning. Isolated yields were at first poor, although the
method was improved significantly using rhodium carbenoid
3130 complexed with Buchwald’s “DavePhos”31 as catalyst.
This procedure gave 27 in yields indicative of multiple
catalyst turnovers. The next question was whether the silylk-
etene aminal putatively formed in situ (namely 26) could
be coaxed to fragment en route to a structure of type 24.
Fluoride treatment of crude hydrosilylation mixtures
decreased the isolated yield of 27, but not productively. We
presumed the NH4PF6 pretreatment used to facilitate con-
version had converted meso-21 into a salt form wherein
26 would be protonated and could self-immolate in situ.
Lewis acids, rather than NH4PF6, were therefore screened as
alternate promoters. When MgBr2 etherate was employed,
we continued to isolate 27, but the major product proved
to be a single diastereomer of polycycle 28, an outcome
rationalized in terms of a Lewis acid-coordinated form of
26 undergoing an internal Mukaiyama-Michael addition.
This unintended result was potentially valuable. The core
diazabicycle in 28 was identical to that targeted in 25, just
lacking halogen on the methano bridge. X-ray diffrac-
tion analysis of crystals grown from samples of SEM-
deprotected 28 showed the desired relative stereochemis-
try throughout the structure. Moreover, treating 28 with
KHMDS efficiently cleaved the hydrazide N-N bond ad-
jacent to the enolizable methine to afford 30. Rendering that
material more like we draw the natural product (as shown)
makes its relation to the original palau’amine assign-
ment clear. One could envision scenarios in which a series
of controlled reductions might achieve that end.
With that topic left for a future date, we returned to the
issue of generating 24. We were unable to steer the hydro-
silylation of meso-21 toward 24 in situ, yet the observa-
tion that 28 cleanly fragmented to 30, presumably via its
potassium enolate, upon KHMDS treatment suggested the
22 f 23 conversion was viable, despite the N-N bond to
be cleaved being oriented near orthogonal to the enolate
π system. We thus treated isolated 27 with KHMDS. Unlike
28, this caused extensive decomposition. However, if we
dissolved 27 in DMF and added 1 equiv of anhydrous LiCl,
followed by DBU,32 we could isolate a ring-opened material
in good yield. Unfortunately, ring-opening occurred cleanly
within the oxidized “half” to afford extended chromophore
32 as a canary yellow solid (Scheme 7).
Enolizing a monoreduced dimer was evidently not a
method to accesss 24. While paths to circumvent the problem
seemed available, our next move was actually dictated by
external events. In early 2007, a succession of papers called
into question Scheuer’s original assignment of palau’amine
relative stereochemistry.16 Characterization of newly discov-
ered relatives, along with reinterpretation of spectroscopic
data collected on palau’amine itself, suggested the molecule
was epimeric at carbons 12 and 17, wherein 1b (Figure 1)
(29) Ojima, I.; Kogure, T.; Nagai, Y. Tetrahedron Lett. 1972, 5035.
(30) Voutchkova, A. M.; Appelhans, L. N.; Chianese, A. R.; Crabtree, R.
H. J. Am. Chem. Soc. 2005, 127, 17624–17625.
(31) Anderson, K. W.; Buchwald, S. L. Angew. Chem., Int. Ed. 2005, 44,
6173–6177.
(32) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune,
S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183–2186.
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SCHEME 6. (A) Initial Strategy To Parlay Dimers 21 into Palau'amine Intermediates with Control of Relative Stereochemistry. (B) Additional
Synthetic Routesa
aReaction conditions: (a) NH4PF6 pretreatment; 20 mol % of (Ph3P)3RhCI, PhMe2SiH (1.1 equiv), CH2Cl2, 45 °C, 24 h; (b) NH4PF6 pretreatment; 5 mol % of 31,
5 mol % of 2-(dicyclohexylphosphino)-20-(N,N-dimethylamino)biphenyl, PhMe2SiH (1.1 equiv), MgI2 (0.8 equiv), CH2Cl2, 45 °C, 18 h (60% 27 + 11% 28); (c)
same as (b) except NH4PF6 treatment omitted and MgBr2 Et2O (1.5 equiv) used in place of MgI2 (45% 28 + 30% 27); (d) KHMDS (2.1 equiv), THF, -78 °C to rt,
3
1 h, 85%; (e) BF3 Et2O (5 equiv), CH2Cl2, 0 °C to rt, 3.5 h; satd NaHCO3, 80%. X-ray structure of 29 shown in ORTEP format (30% probability thermal ellipsoids,
3
hydrogen atoms omitted for clarity).
would be the true form of the natural product. Diastereomer
1b was a fascinating variant and fortunately, one of nu-
merous potential stereochemical outcomes downstream of a
3 f 4 oxidation (Figure 1). Up to this point, we had targeted
24 as a halogenation substrate intending to enforce an
“all syn” substituent array about the cyclopentane core as
5914 J. Org. Chem. Vol. 74, No. 16, 2009

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SCHEME 7a
(Scheme 8B), rather than the deprotonation of Ha that
presumably affords 35.34 While we have yet to characterize
36 crystallographically, all spectroscopic measurements as
well as mass spectra are consistent with the assignment.
Note that the C17H/C18H cis (J=3.9 Hz) stereochemistry
proposed in 36 differs from 35. Our initial argument that the
hydrazide constraint in 24 would be required to establish this
arrangement seems in error. That said, several reaction
variables are ambiguous: the reacting alkylidene geometry,
the reversibility of the spirocyclization, and the identity
of the halogen transfer species. Nevertheless, upon chlorina-
tion we find crude mixtures contain alkylidene 35 having
data consistent with C17/C18 trans stereochemistry, whereas
isolated polycycles 36 display the corresponding substituents
in a cis relation. A lack of coupling between C11H and
C12H and a weak NOESY correlation between C11H and
the C13 methylene protons imply C11/C12 trans stereo-
chemistry in 36 and, to the extent the diazabicyclooctane
motif can be assumed cis fused, the C16 C-N bond would
be oriented β.
aReaction conditions: (a) 1.3 equiv of DBU, 1.2 equiv of LiCl, DMF, 50 °C,
3 h (70%).
Another intriguing finding was made using MgBr2 Et2O
3
assigned in 1a. If 1b were the natural product, the N-N
bond in 24 would be an unnecessary constraint and we
could simply target symmetric bis-alkylidenes 3 as per the
generic plan.
in place of MgCl2 during the halogenation. In that case, we
obtained only 38, wherein C17 was substituted with bromine
rather than chlorine.35 The yield of product had nearly
tripled, and the corresponding alkylidene 37 could not be
detected in crude reaction mixtures. Like 36, pentabromide
38 was isolated as a mixture of C10 epimers. The major
epimer was treated with Et3BHLi followed by anhydrous
TiF4 powder in toluene to afford a mixture of SEM-depro-
tected hemiaminal isomers.36 We tentatively assign structure
39 to these materials.
This was examined first in the meso series. Altering the
stoichiometry of silane to 2.2 equiv and using a combination
of NH4PF6 and MgI2 additives, rhodium-catalyzed reduc-
tion of meso-21 provided doubly saturated compounds 33 in
high yield (Scheme 8). All three possible stereoisomers were
formed;two meso forms 33a/b along with nonsymmetric
material 33c. This was of no preparative consequence. After
careful experimentation, we found the isomeric mixture
could be treated with excess Cy2BOTf followed by brief
exposure to KHMDS to afford doubly ring-opened bis-
alkylidene 34 in good yield. The reaction generates a mixture
of geometric isomers upon hydrolytic workup; however,
these converge to a single, symmetric form during silica gel
chromatography or standing in chloroform solution at room
temperature. We tentatively assign Z stereochemistry at both
alkenes in 34.33
With 34 in hand, we could examine the central tenant
in our approach;the propensity of such compounds to
form spirocyclic products upon oxidative halogenation.
Gratifyingly, when 34 was dissolved in THF containing
MgCl2, cooled to -78 °C, and treated with freshly prepared
t-BuOCl, we obtained three chlorinated products, and all
data suggests they contain the target spirocyclopentane
motif. Minor product 35 is analogous to the alkylidene
formed in our earlier model studies,9 except the material is
now fully functionalized and properly chlorinated. A vicinal
C17H/C18H coupling constant of 12.8 Hz implies the trans
stereochemistry shown,16 although we have yet to assign
configuration at C16. Interestingly, the major products of
the reaction appear to be C10 epimers of polycycle 36. This
unique structure is rationalized in terms of a rebound addi-
tion of the guanidine unit at N1 to N6 of an acyl iminium
species generated transiently upon spirocycle formation
The above results were encouraging. However, we were
uncertain if comparable reactivity could be observed in the
C2-symmetric series, which is configured appropriately to
reach revised palau’amine structure 1b. Catalyzed hydrosi-
lylation remained an effective method of reducing the dimer,
in this case with C2-21 affording saturated isomers 40
(Scheme 9). However, unlike the synthesis of 34 from 33,
isomers 40 reacted chaotically with KHMDS, giving intract-
ables, both with and without added Cy2BOTf. This was
a persistent difficulty, and considerable time passed before
an alternative was found. Ultimately, treating a CH3CN/
DMF solution of 40 with excess proazaphosphatrane 4237
at ambient temperature provided doubly ring-opened, par-
tially debrominated bis-alkylidene 43. If care was taken
to avoid decomposition during isolation, it was possible
to obtain 43 in 40% yield, contaminated with only trace
impurities. We know of no precedent for this remarkable
process wherein two N-N σ bonds are cleaved and two
heteroaryl carbon bromine bonds are reduced in a single
operation.
(34) We have yet to observe products consistent with N5 trapping of the
iminium species in B (Scheme 8). However, it is possible that 35 is a ring-
opened product derivative of such a pathway.
(35) The reaction of t-BuOCl with MgBr2 to generate Br-Cl in situ is one
rationale for this result.
(36) We are not aware of precedent for TiF4-mediated SEM group
removal. Conventional methods were ineffective in this case.
(37) Wroblewski, A. E.; Verkade, J. G. J. Org. Chem. 2002, 67, 420–425.
(38) The reduction of 21 (C2) to diastereomers 40 can also be accom-
plished using Zn dust in refluxing AcOH/THF. This provides 40 (40% yield)
along with mono reduced material (20% yield, analogous to 27) after 30 min
in the presence of 4 equiv of Zn. Extended reaction times or a larger excess of
Zn leads to partial debromination.
3
(33) Attempts to assign olefin geometry in this system using JCH
couplings were inconclusive. Z stereochemistry was thus inferred by analogy;
see: Guella, G.; Mancini, I.; Zibrowius, H.; Pietra, F. Helv. Chim. Acta 1989,
72, 1444–1450.
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SCHEME 8a
aReaction conditions: (a) NH4PF6 pretreatment; 5 mol % of 31, 5 mol % of 2-(dicyclohexylphosphino)-20-(N,N-dimethylamino)biphenyl, PhMe2SiH (2.1
equiv), MgI2 (0.5 equiv), CH2Cl2, 55 °C, 18 h (33a + 33b:33c = 4:1, 82%); (b) 3 equiv of Cy2BOTf, 4.8 equiv of KHMDS THF, -78 °C to rt, 20 min (50%);
(c) t-BuOCl (1.1 equiv), MgX2 (1.5 equiv), THF/CH2Cl2, -78 °C, 2 h (when X = Cl: 26% of 36 + 8% of 35 + 30% of 34; when X = Br: 70% of 38, 37 not
detected); (d) Et3BHLi (5 equiv), toluene, -78 °C (70%); (e) TiF4 (10 equiv), CH2Cl2, sealed vial, 80 °C, 30 min (80%). Structure 33b has been characterized
by X-ray crystallography.
Bis-alkylidene 43 is prone to decomposition, al-
though when pure, the material could be dissolved in
cold CH2Cl2 and treated with t-BuOCl to generate
spirocyclic monoalkylidene 44. In contrast to reactions
in the meso series, added MgCl2 or MgBr2 was neither
beneficial nor steered the outcome toward poly-
cycles analogous to 36. In fact, Lewis acidic additives
were generally detrimental. Our best result employed
t-BuOCl alone, affording 44 in 20-32% yield, with the
mass balance being intractable, seemingly oligomeric
materials.
This result validates our thesis, and despite low yields at
present, we anticipate optimizations. Chloride 44 is the sole
isolable product from the oxidation, which is the tenth linear
step in our sequence. The C17H/C18H trans relation is
supported by a vicinal coupling constant of 11.6 Hz.16 The
C18H/C12H trans relation is thought to be maintained
during the oxidation and is consistent with ROESY correla-
tions in 44 between C18H and the C13 methylene protons as
well as between C12H and C17H. While the alkylidene
geometry and relative configuration at C16 are not yet
known, the former will likely be inconsequential and the
5916 J. Org. Chem. Vol. 74, No. 16, 2009

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SCHEME 9a
aReaction conditions: (a) NH4PF6 pretreatment; 15 mol % of 41, 17 mol % of 2-(dicyclohexyiphosphino)-2-(N,N-dimethylamino)biphenyl, PhMe2SiH (2.1
equiv), LiI (1.1 equiv), CH2C12, 55 °C, 72 h (82%) (ref 38); (b) 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosophabicyclo[3.3.3]undecane (10 equiv), CH3CN/DMF, rt,
14 h (40%); (c) t-BuOCl (1.2 equiv), CH2Cl2, -78 °C, 1 h (20-32%). One diastereomer of 40 has been characterized by X-ray crystallography (ref 17).
latter potentially adjustable (via equilibration) in the context
of more complete intermediates.39,40 Most importantly, con-
fident that bis-alkylidenes of type 34/43 can be precursors to
the halogenated core common to palau’amine and its rela-
tives, we can now focus on tactical refinements needed for
total syntheses. These include substrate modifications to (1)
better manage stability and basicity of intermediates, (2)
permitmorereadyunveilingof free guanidine functionality41,
(3) tunably dictate stereochemical outcomes, and (4) generate
optically active end products. Studies along these lines are
ongoing.
Experimental Section
Pyrrole Monomer 20. A mixture of 19 (34 g, 50 mmol), HgCl2
(19 g, 67 mmol), and pyridine (12.1 mL, 150 mmol) in CH3CN
(250 mL) was heated at reflux for 3 h. A second portion of
HgCl2 (2.7 g, 13.4 mmol) was added and reflux continued for 1 h.
Upon cooling the mixture to rt, a white solid was removed by
filtration and the solvent was evaporated in vacuo. The reac-
tion mixture was taken up in EtOAc, and the undissolved
solids were removed by filtration. The organic layer was washed
with 1 N NaOH, whereupon a white precipitate formed. The
precipitate was filtered, and the NaOH wash/filtration sequence
continued until no further solid formed (6-7ꢀ). The organic
layer was then washed with water and brine and dried over
NaSO4. Concentration in vacuo and purification by silica gel
chromatography (1:3 EtOAc/hexanes) afforded 20 as a white
foam (15.0 g). Mixed fractions were purified on a second silica gel
column (1:9 EtOAc/CH2Cl2) toprovide a further 5.0 g of20 (total
yield=70%): Rf=0.7 (1:9 CH3CN/CHCl3); IR (film) 2951, 1741,
(39) In future iterations of the route (see ref 41), one path forward could
entail transforming a structure of type 44 into an aminoimidazole of type 50.
Installation of the dipyrrolopyrazinone motif required to complete palau’a-
€
mine would then parallel Buchi’s phakellin synthesis (ref 40). Presuming that
process would involve 51 as an intermediate, an equilibrium established with
52 (analogous to the species thought generated from 43 en route to 44) prior
to C10-N2 bond formation would render mute C16 stereochemistry in 44.
We look forward to exploring these issues in detail.
1635, 1402, 1093, 859, 758, 793 cm-1 1H NMR (400 MHz,
;
CD3CN) δ 7.38-7.28 (m, 4H), 6.81 (s, 1H), 5.82 (t, J=4.7 Hz,
1H), 5.60 (s, 2H), 4.89 (s, 2H), 4.66 (s, 2H), 3.92-3.75 (m, 2H),
3.57 (t, J=12 Hz, 2H), 2.33 (dd, J=5.3, 10.4 Hz, 2H), 0.88 (t, J=
12 Hz, 2H), 0.0 (s, 9H); 13C NMR (100 MHz, CD3CN): δ 163.8,
159.3, 141.6, 141.4, 134.9, 129.5, 129.2, 129.1, 129.0, 126.3, 118.7,
118.0, 112.6, 104.2, 100.2, 76.1, 66.7, 49.5, 45.7, 43.6, 23.5, 18.2,
-1.3; HRMS (ESI-TOF) calcd for C25H30Br2N5O3Si (M+H)+
634.0479, found 634.0483.
Meso and C2 Symmetric Dimers 21. Monomer 20 (311 mg,
0.49 mmol) and solid (i-PrCp)2TiCl2 (190 mg, 0.57 mmol) were
dissolved in anhydrous THF (2.5 mL). The brandy-colored
solution was degassed via consecutive freeze-pump-thaw cy-
cles (3ꢀ) and cooled to -78 °C. KHMDS (1.08 mL, 0.5 M in
toluene) was added dropwise, and the resultant dark green
slurry was stirred at -78 °C for 1.5 h. A fine suspension of
Cu(OTf)2 (260 mg, 0.74 mmol) in dry, degassed THF was added
€
(40) Foley, L. H.; Buchi, G. J. Am. Chem. Soc. 1982, 104, 1776–1777.
(41) The 1,3-benzodiazepine ring system used to mask guanidine func-
tions in this work was intended to facilitate oxidative spirocyclization,
wherein substrates 34/43 might adopt compact globular forms in high
dielectric solvents, juxtaposing the tethered alkylidenes. To date, we see no
evidence for such behavior nor have we succeeded in degrading the benzo-
diazepine units to the corresponding free glycocyamidines in various inter-
mediate settings. Alternatives are being pursued.
J. Org. Chem. Vol. 74, No. 16, 2009 5917

Li et al.
JOCArticle
over 15 min, and the dark red/brown slurry stirred at -78 °C for
3 h and then at rt for 1.5 h. The reaction was treated with pH
8.0 aq EDTA (5 mL, 0.35 M), and the volatiles were removed in
vacuo. The residue was diluted in EtOAc and washed with
additional pH 8.0 EDTA solution (until blue color no longer
observed), H2O, and brine. The organics were dried over Na2SO4,
filtered, and concentrated. Purification by column chromatogra-
phy on silica gel (1% CH3CN/CHCl3) afforded meso-21 (150 mg,
49%) and C2-21 (45 mg, 15%). meso-21: light yellow solid; Rf=
0.35 (10% CH3CN/CHCl3); IR (film) 1745, 1745, 1698, 1447,
1396, 1093, 934, 836 cm-1; 1H NMR(400 MHz, CD3CN, 70 °C) δ
7.40-7.20 (m, 8H), 6.71 (s, 2H), 5.66-5.48 (m, 6H), 4.95 (s, 4H),
4.62 (s, 4H), 3.77 (bs, 4H), 3.57 (t, J=8.0 Hz, 4H), 2.49 (s, 2H),
0.86 (t, J=8.0 Hz, 4H), 0.01 (s, 18H); 13C NMR (75 MHz, CDCl3,
55 °C) δ 163.0, 158.4, 140.7, 140.2, 133.6, 130.3, 129.3, 128.8,
128.7, 128.5, 125.3, 118.0, 112.4, 104.0, 100.2, 75.6, 66.5, 49.6,
45.6, 43.6, 36.5, 18.2, -1.2; HRMS (ESI-TOF) calcd for
C50H57Br4N10O6Si2 (M+H)+ 1265.0729, found 1265.0730. Crys-
tals of meso-21 suitable for X-ray diffraction were grown from
MeOH (slow evaporation). Details of the crystallographic analy-
sis are provided in a separate CIF file (Supporting Information).
C2-21: light yellow solid; Rf = 0.2 (10% CH3CN/CHCl3); IR
Hz, 1H), 3.81 (dd, J = 11.6, 4.9 Hz, 1H), 3.59 (t, J=8.1 Hz,
2H), 3.57 (t, J=8.1 Hz, 2H), 3.26 (dd, J=12.9, 5.3 Hz, 1H), 2.33
(t, J = 12.2 Hz, 1H), 2.18-2.16 (m, 1H), 1.91-1.86 (m,
1H), 1.78-1.69 (m, 2H), 1.28-1.21 (m, 1H), 1.04 (q, J = 12.2
Hz, 1H), 0.97-0.82 (m, 4H), 0.01 (s, 9H), 0.00 (s, 9H); 13C NMR
(100 MHz, CD3CN) δ 172.1, 171.3, 164.9, 164.6, 149.1, 148.0,
135.8, 135.7, 130.8, 130.7, 130.3, 130.2, 130.0, 129.9, 128.7, 128.5,
118.3, 111.8, 111.5, 100.8, 100.7, 77.5, 67.9, 58.0, 50.5, 50.3, 45.1,
44.9, 34.8, 34.4, 31.9, 27.9, 19.6, 19.5, -0.4; HRMS (ESI-TOF)
calcd for C50H61Br4N10O6Si2 (M + H)+ 1269.1042, found
1269.1038.
Symmetric Bis-alkylidene 43. A flame-dried 5 mL flask was
charged with 40a or 40b (100 mg, 78.6 μmol), DMF (830 μL), and
CH3CN (330 μL) at rt. 2,8,9-Triisobutyl-2,5,8,9-tetraaza-1-
phosphabicyclo[3.3.0]undecane (269 mg, 786 μmol) was added,
and the resulting mixture was stirred at rt for 22 h. The dark
reddish purple mixture was diluted with EtOAc and washed with
saturated aqueous NH4Cl, water, saturated aqueous NaHCO3,
water, and brine. The organic layer was dried over Na2SO4,
filtered, and concentrated in vacuo. The crude residue was
purified by column chromatography on silica gel slurry packed
(1%Et3N-CH2Cl2) andeluted (2%MeOH-CH2Cl2) togive the
desired product in yields ranging from 30 to 50%. Pure 43 was
obtained using HPLC (5 μm C-18 column, 250ꢀ10 mm, 85%
CH3CN/H2O, 8 mL/min, UV detection at 254 nm; tR=6.0 min):
1H NMR (500 MHz, CD3CN) δ 7.48 (bs, 2H), 7.42-7.31 (m,
8H), 6.97 (d, J=1.8 Hz, 2H), 6.63 (d, J = 1.8 Hz, 2H), 5.60 (d, J=
10.2 Hz, 2H), 5.51 (d, J=9.2 Hz, 2H), 5.42 (d, J=10.2 Hz, 2H),
4.91(d, J=18.2 Hz, 2H), 4.88 (d, J=18.2Hz, 2H), 4.62(d, J=14.9
Hz, 2H), 4.52 (d, J=14.8 Hz, 2H), 3.46-3.38 (m, 6H), 3.18-3.06
(m, 4H), 0.79-0.70 (m, 4H), -0.12 (s, 18H); 13C NMR (100
MHz, CD3CN) δ 167.5, 161.6, 140.3, 136.5, 130.3, 130.0, 129.7,
128.7, 127.4, 116.2, 115.9, 96.4, 77.7, 67.1, 46.1, 44.2, 41.7, 30.8,
18.7, 18.6, 0.0; MS calcd for C50H63Br2N10O6Si2 (ESI+) m/z
(relative intensity) 1115.30, found 1115.00.
Spirocyclic Alkylidene Chloride 44. Symmetric bis-alkylidene
43 (18 mg, 16.1 μmol) was dissolved in CH2Cl2 (150 μL), and the
resulting solution was cooled to -78 °C. A stock solution of tert-
butyl hypochlorite (20 μL) in CH2Cl2 (500 μL) was prepared
fresh at rt prior to use. A 50 μL portion of this stock solution was
added to the solution of 43, and stirring was continued at -78 °C
for 10 min. After being warmed to rt, the mixture was diluted
with CH2Cl2 and washed with saturated aq NaHCO3. The
organic layer was dried over Na2SO4, filtered, and concentrated
in vacuo. Purification by preparative thin-layer chromatogra-
phy (9% MeOH/CH2Cl2) gave 6.4 mg (36%) of 44. Pure 44 was
obtained after HPLC: analytical (5 μm C-18 column, 250ꢀ4.6
mm, 85% CH3CN/H2O, 1 mL/min, UV detection at 254 nm,
tR=13.3 min); preparative (5 μm C-18 column, 250 ꢀ 10 mm,
85% CH3CN/H2O, 8 mL/min, UV detection at 254 nm, tR =
7.5 min); 1H NMR (500 MHz, CD3CN) δ 8.15 (s, 1H), 7.48-
7.45 (m, 1H), 7.42-7.36 (m, 2H), 7.35-7.26 (m, 6H), 7.02 (d,
J=1.9 Hz, 1H), 7.00 (d, J=1.9 Hz, 1H), 6.83 (d, J=1.7 Hz, 1H),
6.75 (d, J=1.9 Hz, 1H), 5.61 (d, J=10.3 Hz, 1H), 5.59 (d, J=10.4
Hz, 1H), 5.58 (d, J = 10.3 Hz, 1H), 5.56 (d, J = 10.3 Hz, 1H),
4.92 (s, 2H), 4.73 (s, 2H), 4.56 (d, J=14.8 Hz, 1H), 4.49 (d, J=
15.0 Hz, 1H), 4.49 (d, J=15.0 Hz, 1H), 4.38 (d, J=15.0 Hz, 2H),
4.01 (d, J=11.6 Hz, 1H), 3.77 (ddd, J=13.1, 4.3, 4.3 Hz, 1H),
3.65 (ddd, J=14.3, 6.0, 4.3 Hz, 1H), 3.49-3.38 (m, 4H), 3.46 (t,
J=2.0 Hz, 2H), 3.13 (ddd, J = 8.8, 4.1, 4.1 Hz, 1H), 2.32-2.25
(m, 1H), 0.79 (t, J=2.0 Hz, 2H), 0.77-0.71 (m, 2H), -0.10 (s,
9H), -0.14 (s, 9H); 13C NMR (100 MHz, CD3CN): δ 178.9,
166.5, 162.5, 162.4, 158.9, 158.7, 140.3, 139.8, 138.5, 136.6,
136.4, 130.8, 130.3, 130.2, 130.1, 129.9, 129.8, 129.7, 129.3,
129.0, 128.3, 127.8, 127.3, 116.8, 116.5, 96.4, 96.3, 78.0, 77.6,
76.6, 69.7, 67.2, 67.0, 47.8, 46.0, 45.7, 45.2, 45.0, 44.1, 42.9, 40.2,
18.6, -1.0; HRMS (ESI-TOF) calcd for C50H63Br2ClN10O6Si2
(M+H)+ 1147.2442, found 1147.2432.
1
(film) 1745, 1698, 1448, 1397, 1093, 934, 836 cm-1; H NMR
(400 MHz, CD3CN, 70 °C) δ 7.40-7.20 (m, 8H), 6.72 (s, 2H),
5.72 (s, 2H), 5.51(s, 4H), 4.95 (s, 4H), 4.61(S, 4H), 3.87 (bs, 4H),
3.58 (t, J=8 Hz, 4H), 2.49 (s, 2H), 0.86 (t, J=8 Hz, 4H), 0.01 (s,
18H); 13C NMR (75 MHz, CDCl3, 55 °C) δ 163.0, 158.5, 140.7,
140.2, 133.6, 130.2, 129.3, 128.8, 128.5, 125.0, 118.1, 112.5, 103.7,
100.2, 75.6, 66.6, 49.6, 46.4, 43.6, 36.7, 18.2, -1.2; HRMS (ESI-
TOF) calcd for C50H57Br4N10O6Si2 (M+H)+ 1265.0729, found
1265.0707.
Catalyzed Reduction of Dimer C2-21 to 40. A 25 mL flame-
dried flask was charged with C2-21 (2.0 g, 1.58 mmol), NH4PF6
(770 mg, 4.72 mmol), LiI (233 mg, 1.74 mmol), and THF
(7.9 mL), and the mixture was stirred at rt for 10 min. The solvent
was removed in vacuo. A separate 25-mL flame-dried flask was
charged with 100 mg of cyclooctadiene N,N-dimethylimidazo-
lium rhodium(I) iodide 41 (0.24 mmol, 15 mol %), 2-dicyclohexyl-
phosphino-20-(N,N-dimethylamino)biphenyl (102 mg, 0.26 mmol,
17 mol %), and CH2Cl2 (7.9 mL). PhMe2SiH (644 mg, 4.72 mmol)
was added, and the resulting solution was stirred at rt for 5 min.
This catalyst solution was added to the flask containing 21, and the
resulting suspension was heated at 50 °C for 72 h. Upon cooling to
rt, the reaction mixture was quenched with saturated NaHCO3 and
diluted with CH2Cl2. The aqueous layer was separated and
extracted with CH2Cl2. The combined organics were dried over
MgSO4, filtered, and concentrated in vacuo. Purification via
column chromatography on silica gel (gradient from 5% f 50%
CH3CN/CHCl3) gave 928 mg of 40a that was roughly 60% pure.
This was followed by 40b (840 mg, 42%). Pure40a was obtained by
triturating with CH3CN (yield ∼30%): 1H NMR (500 MHz,
CDCl3) δ 7.37-7.25 (m, 8H), 6.82 (s, 2H), 5.81 (d, J=10.5 Hz,
2H), 5.36 (d, J=10.5 Hz, 2H), 4.90 (d, J=19.2 Hz, 2H), 4.87
(d, J=19.2 Hz, 2H), 4.73 (d, J=19.2 Hz, 2H), 4.70 (d, J=19.2 Hz,
2H), 4.45 (d, J = 12.8 Hz, 2H), 3.73-3.70 (m, 2H), 3.62 (dd,
J = 11.6, 4.5 Hz, 2H), 3.45 (ddd, J = 9.0, 6.9, 1.9 Hz, 4H), 2.49
(dd, J = 12.7, 11.3 Hz, 2H), 2.11-2.08 (m, 2H), 1.59-1.54
(m, 2H), 1.20-1.07 (m, 2H), 0.89-0.74 (m, 2H), -0.06 (s, 18H);
13C NMR (100 MHz, CDCl3) δ 169.4, 163.7, 145.1, 140.1,
133.0, 129.4, 128.6, 128.5, 128.4, 128.3, 125.2, 117.3, 111.0,
99.4, 75.1, 66.1, 56.2, 49.2, 43.3, 34.9, 29.9, 17.9, -1.4; MS
for C50H61Br4N10O6Si2 (ESI+) m/z (relative intensity) 1273
1
(M+ + 1, 100). 40b: H NMR (500 MHz, CD3CN, 70 °C) δ
7.37-7.27 (m, 7H), 7.24-7.20 (m, 1H), 6.77 (s, 1H), 6.75 (s, 1H),
5.61 (d, J = 10.7 Hz, 1H), 5.59 (s, 2H), 5.54 (d, J = 10.7 Hz,
1H), 4.95-4.87 (m, 4H), 4.75 (d, J=14.5 Hz, 1H), 4.70 (d, J = 14.4
Hz, 1H), 4.62 (d, J=14.5 Hz, 1H), 4.60 (d, J= 14.5 Hz, 1H),
4.56-4.43 (m, 1H), 4.12 (t, J = 6.1 Hz, 1H), 4.01 (dd, J= 12.9, 7.3
5918 J. Org. Chem. Vol. 74, No. 16, 2009

Li et al.
Acknowledgment. Funding was provided by the NIH (RO1-
JOCArticle
Note Added after ASAP Publication. This article posted
ASAP on July 16, 2009. Due to
Scheme 3 legend has been revised. The correct version posted on
July 23, 2009.
a production error,
GM60591), the Robert A. Welch Foundation, the Chilton
Family Endowment, the Donald J. & Jane M. Cram Endow-
ment, and unrestricted research awards from Merck and Pfizer.
A large portion of this work was carried out at the University of
Texas Southwestern (UTSW) Medical Center where Q.L. was a
Robert A. Welch Foundation Graduate Fellow. We are grateful
to Drs. Ranny Mathew Thomas, Jian Wang, and Christopher
Lindsey for valuable experimental assistance.
Supporting Information Available: Experimental proce-
dures, characterization data for all new compounds, and crystal-
lographic data for intermediates 12, 13, 21-meso, 29, 33b, and
40a. This material is available free of charge via the Internet at
http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 16, 2009 5919