Asymmetric total syntheses of (-)-jorumycin, (-)-renieramycin G, 3-epi-jorumycin, and 3-epi-renieramycin G

Article abstract of DOI:10.1021/ja0535918

The total synthesis of (-)-jorumycin (1) and (-)-renieramycin G (2) has been accomplished in 25 and 23 steps, respectively, from 5-benzyloxy-2,4- dimethoxy-3-methyl-benzyl alcohol. The synthesis features a substrate-tunable stereoselective intramolecular

Full text of DOI:10.1021/ja0535918

Published on Web 08/19/2005
Asymmetric Total Syntheses of (-)-Jorumycin,
(-)-Renieramycin G, 3-epi-Jorumycin, and
3-epi-Renieramycin G
Jonathan W. Lane, Yuyin Chen, and Robert M. Williams*
Contribution from the Department of Chemistry, and UniVersity of Colorado Cancer Center,
Colorado State UniVersity, Fort Collins, Colorado 80523
Received June 1, 2005; E-mail: rmw@chem.colostate.edu
Abstract: The total synthesis of (-)-jorumycin (1) and (-)-renieramycin G (2) has been accomplished in
25 and 23 steps, respectively, from 5-benzyloxy-2,4-dimethoxy-3-methyl-benzyl alcohol. The synthesis
features a substrate-tunable stereoselective intramolecular Pictet-Spengler-type reaction for the construction
of the key pentacyclic core of both targets, bearing either the natural configuration or the epimeric
configuration at C-3. With access to a C-3 epi-pentacyclic framework, 3-epi-jorumycin (32) and 3-epi-
renieramycin G (34) were also successfully synthesized. Furthermore, preliminary biological evaluation of
3-epi-jorumycin (32), in addition to relevant synthetic intermediates, revealed that significant cytotoxicity
had been retained in these compounds. Therefore, these early studies constitute the basis for a new structure
activity relationship (SAR) investigation for this class of antitumor antibiotics.
Introduction
The antitumor antibiotics belonging to the tetrahydroiso-
quinoline family have been studied thoroughly, and numerous
natural products within the class have been isolated.1 (-)-
Jorumycin (1), a member of this family, was isolated from the
mantle and mucus of the pacific nudibranch Jorunna funebris
(Figure 1).2 (-)-Jorumycin (1) is closely related to the safra-
mycins (6-8), members of the renieramycin family (2-4), and,
most notably, Ecteinascidin 743 (Et)-743 (5), which was
demonstrated to be a highly promising, exceedingly potent
antitumor agent currently in phase II/III clinical trials.3 In
general, the tetrahydroisoquinoline family of alkaloids include
potent cytotoxic agents that display a range of biological
properties such as antitumor and antimicrobial activities.1
Consistent with other members in the group, (-)-jorumycin (1)
also harbors potent biological activities. Specifically, 1 has
shown activity against NIH 3T3 tumor cells (100% of inhibition
at 50 ng/mL) and has displayed cytotoxicity (IC50 12.5 ng/mL)
against other tumor cell lines at very low concentrations.
Additionally, 1 was shown to inhibit the growth of various
Gram-positive bacteria (e.g., Bacillus subtilis, Staphylococcus
aureus) at a concentration lower than 50 ng/mL.2 An efficient
semisynthesis of 1 from a closely related natural product,
renieramycin M (4), was recently reported by Saito and co-
workers.4
Figure 1. Tetrahydroisoquinoline alkaloids.
having an amide carbonyl residue at C-21, 2 was reported to
retain cytotoxicity against human cancer cells with MIC values
of 0.5 and 1.0 µg/mL against KB and LoVo cell lines,
respectively.5 This is surprising in light of the fact that virtually
all biologically active members of this family of tetrahydroiso-
quinoline alkaloids possess a carbinolamine or cyano function
at C-21 that permits the formation of a potent, electrophilic
(-)-Renieramycin G (2) was isolated from the marine sponge
Xestospongia caycedoi by Davidson in 1992 (Figure 1).5 Despite
(1) For a review, see: Scott, J. D.; Williams, R. M. Chem. ReV. 2002, 102,
1669-1730.
(2) Fontana, A.; Cavaliere, P.; Wahidulla, S.; Naik, C. G.; Cimino, G.
Tetrahedron 2000, 56, 7305-7308.
(4) Saito, N.; Tanaka, C.; Koizumi, Y.-i.; Suwanborirux, K.; Amnuoypol, S.;
Pummangura, S.; Kubo, A. Tetrahedron 2004, 60, 3873-3881.
(5) Davidson, B. S. Tetrahedron Lett. 1992, 33, 3721-3725.
(3) Aune, G. J.; Furuta, T.; Pommier, Y. Anti-Cancer Drugs 2002, 13, 545-
555.
9
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J. AM. CHEM. SOC. 2005, 127, 12684-12690
10.1021/ja0535918 CCC: $30.25 © 2005 American Chemical Society

Asymmetric Total Synthesis of (−)-Jorumycin
A R T I C L E S
Scheme 1. Retrosynthetic Analysis
iminium ion species that has been implicated in the formation
of covalent bonds to DNA and possibly other biomacromol-
ecules.1
Previously, our laboratory reported an efficient method for
the construction of a highly functionalized pentacyclic tetrahy-
droisoquinoline relevant to the ecteinascidin, saframycin, sa-
fracin, and renieramycin families of antitumor alkaloids.6a The
approach, which was based on the use of sequential asymmetric
Staudinger and Pictet-Spengler cyclization reactions, ultimately
afforded a pentacyclic core containing an alkene group at the
C3-C4 position (renieramycin numbering). Further employment
of this intermediate in the synthesis of relevant natural product
targets mandates retention of the alkene (for cribrostatin 4),
saturation, or, in the case of the ecteinascidins and bioxalomy-
cins, heteroatom functionalization at C3-C4 position. As part
of a program directed toward efficient, asymmetric total
syntheses of relevant members of the tetrahydroisoquinoline
family,6 improvements were sought with respect to the construc-
tion of a necessarily versatile pentacyclic ring system that would
be of potential use in accessing a variety of these targets. We
report here a general method to construct a saturated pentacyclic
ring system that should prove useful for the asymmetric total
synthesis of several members of this family of natural products
and congeners. The utility of this approach is demonstrated here
through the first asymmetric total syntheses of (-)-jorumycin
(1) and (-)-renieramycin G (2). Furthermore, en route to 1 and
2, a serendipitous discovery afforded a method to efficiently
and selectively access a related pentacyclic intermediate,
epimeric at the C-3 position. The C-3-epi-pentacycle was
subsequently employed in the synthesis of 3-epi-jorumycin (32)
and 3-epi-renieramycin G (34). The biological activity of this
hitherto unreported stereochemical series is also reported herein.
Our strategy for the total synthesis of (-)-jorumycin (1) and
(-)-renieramycin G (2) is illustrated in Scheme 1. Nucleophilic
coupling between the appropriately functionalized aryl iodide
10 and chiral glycine template 97,10 would afford intermediate
11. Based on the intrinsic symmetry of 1 and 2, coupling
partners 12 and 13, representing the western and eastern halves
of our targets, respectively, can both be derived from 11.
Importantly, compound 12 will bear full saturation at the C3-
C4 position (renieramycin numbering), obviating the difficult
reduction required through our previous approach.6a Cyclization
substrate 14 would be available through a convergent coupling
between intermediates 12 and 13 followed by oxidation at the
appropriate primary alcohol position. An intramolecular Pictet-
Spengler condensation through the aldehyde group of intermedi-
ate 14 would provide the versatile pentacyclic intermediate 15.
Our intermediate 15 would provide 1 or 2 through straightfor-
ward functional group manipulations and should prove useful
in the synthesis of related targets and their congeners.
Results and Discussion
Historically, numerous synthetic efforts toward members of
the saframycin and renieramycin families of antitumor anti-
biotics have exploited a symmetry-based approach.8 Such a
strategy is logical because, unlike Et-743 which contains a
pseudo-symmetrical pentacyclic core,6a,b,9 the saframycins and
renieramycins possess a symmetrical substitution pattern on both
the eastern and the western arene units. Indeed, the notion of
employing a single common intermediate in a stereoselective
and highly symmetrical approach toward any member of the
saframycin or renieramycin families was pioneered by Myers
(9) For synthetic approaches to Et-743 and congeners, see: (a) Corey, E. J.;
Gin, D. Y.; Kania, R. J. Am. Chem. Soc. 1996, 118, 9202-9203. (b)
Martinez, E. J.; Corey, E. J. Org. Lett. 2000, 2, 993-996. (c) Martinez, E.
J.; Owa, T.; Schreiber, S. L.; Corey, E. J. Proc. Natl. Acad. Sci. U.S.A.
1999, 96, 3496-3501. (d) Endo, A.; Yanagisawa, A.; Abe, M.; Tohma,
S.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 6552-6554. (e)
Cuevas, C.; Pe´rez, M.; Mart´ın, M. J.; Chicharro, J. L.; Ferna´ndez-Rivas,
C.; Flores, M.; Francesch, A.; Gallego, P.; Zarzuelo, M.; de la Calle, F.;
Garc´ıa, J.; Polanco, C.; Rodr´ıguez, I.; Manzanares, I. Org. Lett. 2000, 16,
2545-2548. (f) Menchaca, R.; Mart´ınez, V.; Rodr´ıguez, A.; Rodr´ıguez,
N.; Flores, M.; Gallego, P.; Manzanares, I.; Cuevas, C. J. Org. Chem. 2003,
68, 8859-8866. (g) Saito, N.; Toshiro, K.; Maru, Y.; Yamaguchi, K.; Kubo,
A. J. Chem. Soc., Perkin Trans. 1 1997, 53-69. (h) Saito, N.; Kamayachi,
H.; Tachi, M.; Kubo, A. Heterocycles 1999, 51, 9-12. (i) Saito, N.; Tachi,
M.; Seki, R.-I.; Kamayachi, H.; Kubo, A. Chem. Pharm. Bull. 2000, 48,
1549-1557. (j) Saito, N.; Seki, R.-I.; Kameyama, N.; Sugimoto, R.; Kubo,
A. Chem. Pharm. Bull. 2003, 51, 821-831. (k) Zhou, B.; Guo, J.;
Danishefsky, S. J. Tetrahedron Lett. 2000, 41, 2043-2046. (l) Zhou, B.;
Edmondson, S.; Padron, J.; Danishefsky, S. J. Tetrahedron Lett. 2000, 41,
2039-2042. (m) Zhou, B.; Guo, J.; Danishefsky, S. J. Org. Lett. 2002, 4,
43-46. (n) Tang, Y.; Liu, Z.; Chen, S. Chin. Chem. Lett. 2003, 14, 1-2.
(o) Tang, Y.; Liu, Z.; Chen, S. Tetrahedron Lett. 2003, 44, 7091-7094.
(p) De Paolis, M.; Chiaroni, A.; Zhu, J. Chem. Commun. 2003, 23, 2896-
2897. (q) Chen, X.; Chen, J.; De Paolis, M.; Zhu, J. J. Org. Chem. 2005,
70, 4397-4408.
(6) (a) Jin, W.; Metobo, S.; Williams, R. M. Org. Lett. 2003, 5, 2095-2098.
(b) Jin, W.; Williams, R. M. Tetrahedron Lett. 2003, 44, 4635-4639. (c)
Herberich, B.; Kinugawa, M.; Vazquez, A.; Williams, R. M. Tetrahedron
Lett. 2001, 42, 543-546.
(7) (a) Williams, R. M.; Im, M.-N. Tetrahedron Lett. 1988, 29, 6075-6078.
(b) Williams, R. M.; Im, M.-N. J. Am. Chem. Soc. 1991, 113, 9276-9286.
(c) Williams, R. M. Aldrichimica Acta 1992, 25, 11-25. (d) Bender, D.
M.; Williams, R. M. J. Org. Chem. 1997, 62, 6690-6691. (e) Dastlik, K.
A.; Sundermeier, U.; Johns, D. A.; Chen, Y.; Williams, R. M. Synlett 2005,
4, 693-696.
(8) (a) Myers, A. G.; Kung, D. W. J. Am. Chem. Soc. 1999, 121, 10828-
10829. (b) Myers, A. G.; Lanman, B. A. J. Am. Chem. Soc. 2002, 124,
12969-12971. (c) Myers, A. G.; Kung, D. W. Org. Lett. 2000, 2, 3019-
3022. (d) Myers, A. G.; Plowright, A. T. J. Am. Chem. Soc. 2001, 123,
5114-5115. (e) Fukuyama, T.; Sachleben, R. A. J. Am. Chem. Soc. 1982,
104, 4957-4958. (f) Fukuyama, T.; Yang, L.; Ajeck, K. L.; Sachleben, R.
A. J. Am. Chem. Soc. 1990, 112, 3712-3713. (g) Fukuyama, T.; Linton,
S. D.; Tun, M. M. Tetrahedron Lett. 1990, 31, 5989-5992. (h) Kubo, A.;
Saito, N.; Yamauchi, R.; Sakai, S. Chem. Pharm. Bull. 1987, 35, 2158-
2161. (i) Saito, N.; Yamauchi, R.; Nishioka, H.; Ida, S.; Kubo, A. J. Org.
Chem. 1989, 54, 5391-5395. (j) Shawe, T. T.; Liebeskind, L. S.
Tetrahedron 1991, 47, 5643-5666. (k) Ong, W. O.; Chang, Y. A.; Wu,
J.-Y.; Cheng, C.-C. Tetrahedron 2003, 59, 8245-8249.
(10) Both antipodes of 9 are commercially available from Aldrich Chemical
Co.: 9, catalog #33, 184-8; antipode of 9, catalog #33, 181-3.
9
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A R T I C L E S
Lane et al.
Scheme 2. Synthesis of Tyrosine Derivative 19
Scheme 3. Construction of Tetrahydroisoquinoline 25
and co-workers in their elegant total synthesis of (-)-saframycin
A.8a The efficiency of this strategy ultimately culminated in a
viable solid-phase route to saframycin A and analogues.8b
Our universal building block, compound 11, was readily
available through straightforward methods (Scheme 2).6b Ini-
tially, alcohol 168e was converted to the corresponding benzyl
iodide derivative 10 in quantitative yield. However, compound
10 was found to be unstable and was therefore utilized crude
through immediate condensation with the sodium enolate of
oxazinone 9 to afford the alkylation product 11 in 88% yield.7,10
Conversion of compound 11 to the requisite amino acid
component 13 (Scheme 1), representing the eastern half of 1
and 2, proceeded as follows. The O-benzyl group of 11 was
initially removed by catalytic hydrogenation to give the corre-
sponding phenol, followed by removal of the N-t-Boc protecting
group by treatment with TFA to afford an amine intermediate.
Subsequent reprotection of the phenol group of this intermediate
as the corresponding O-TBS ether under standard conditions
afforded compound 17 in 75% for three steps. The requisite
N-Me group was then installed through reductive amination of
the secondary amine group in 17 producing N-methyl lactone
18 in 72% yield. Removal of the chiral auxiliary in compound
18 by catalytic hydrogenation, followed by protection of the
secondary amine as the corresponding Fmoc derivative, fur-
nished amino acid 19 in 77% yield for two steps.
With the eastern tyrosine derivative in hand, synthesis of
tetrahydroisoquinoline component 12, representing the western
half of 1 and 2, commenced as above, from compound 11
(Scheme 3). Initially, subjection of compound 11 to catalytic
hydrogenation conditions affected removal of the O-benzyl
group as well as partial cleavage of the chiral auxiliary, affording
a carboxylic acid intermediate. The carboxylic acid group in
this intermediate was subsequently converted to the correspond-
ing primary alcohol through a mixed-anhydride reduction
producing compound 20 in 88% yield for two steps. Removal
of the N-t-Boc protecting group in compound 20 by treatment
with TFA followed by selective protection of the free primary
alcohol as the corresponding O-TBS ether under standard
conditions afforded compound 21 in 88% yield for two steps.
Treatment of this substance with ethyl glyoxylate afforded the
corresponding anti-tetrahydroisoquinoline 22 as a single ster-
eoisomer in 92% yield.
Consistent with prior observations regarding peptide couplings
of similarly functionalized amine substrates with sterically
demanding carboxylic acid partners,6a a syn relationship with
respect to the C-1 and C-3 positions was determined to be
required for a successful marriage of the eastern and western
core units. Therefore, equilibration of the anti-carboethoxy group
in 22 with DBU9p,q afforded an inseparable (3.3:1) mixture of
diastereomers in favor of the ester intermediate bearing the
desired syn configuration at C-1. Conversion of the ester group
in this intermediate to the corresponding primary alcohol was
accomplished by subjecting the product mixture to reductive
conditions (LiBH4), successfully producing compound 23 (dr
3.3:1) in 89% yield. Exchange of the chiral auxiliary in
compound 23 for the corresponding N-t-Boc protecting group
was accomplished in one step by hydrogenolysis of the isomeric
mixture in the presence of Boc2O. This operation afforded the
desired substance 24 in 69% yield in addition to 23% of the
corresponding anti-isomer, which, at this juncture, were easily
separated by conventional flash chromatography. In addition
to providing a pair of chromatographically separable isomers,
the functional group exchange installed appropriate, temporary
protection at the nitrogen position on compound 24. Nitrogen
protection was found to be essential for subsequent protecting
group installation at the two remaining free alcohol positions,
and, furthermore, the N-t-Boc group could be easily removed
under conditions compatible with the overall protection strategy.
Therefore, bis-allyl protection of the free alcohol positions in
compound 24 afforded a fully protected carbamate intermediate.
Finally, the N-t-Boc group was selectively removed under
Lewis-acid conditions, producing compound 25 in excellent
yield for two steps. Importantly, the allyl ether groups were
chosen for their orthogonal characteristics with respect to the
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Asymmetric Total Synthesis of (−)-Jorumycin
A R T I C L E S
Scheme 4. Construction of 3-epi-Pentacycle 28
Figure 2. X-ray structure of 3-epi-pentacycle 28.
workers, in their groundbreaking total synthesis of Et-743,
deployed a hemi-aminoacetal derivative to effect a C19-C11
bond-forming process that selectively cyclized to a key penta-
cyclic intermediate bearing the natural configuration at C-3.9a,b
Although the C3-epi cyclization conundrum posed an initial
obstacle with respect to the synthesis of 1 and 2, the efficient
route to compound 28 fortuitously presented a unique op-
portunity. Indeed, selective access to a pentacyclic intermediate
bearing the opposite configuration at C-3 would, in turn, provide
a gateway to a hitherto unexplored series of C3-epi-tetrahy-
droisoquinoline natural product analogues. Structure-activity
relationships (SARs) have been reported on potent analogues
of saframycin A (6) by Myers and co-workers,8b,d and Corey,
Schreiber, and co-workers have prepared synthetic analogues
of Et-743 (5) (e.g., phthalascidin, Pt-650) that maintained
virtually the same cytotoxicity as the parent natural product.9c
Additionally, studies by Ong and co-workers toward the
development of a pentacyclic scaffold mimic of saframycin A
resulted in a compound of diminished potency with respect to
the parent natural product.8k However, to date SAR investiga-
tions have not addressed the cytotoxicity profiles of epimeric
members of the tetrahydroisoquinoline family bearing the
pentacyclic skeleton characteristic of the saframycins. The
specific global conformations of these compounds will most
likely reflect the individual stereochemical configurations
contained within the pentacyclic system. Therefore, one could
hypothesize that a structural modification of this variety could
manifest into a significantly altered backbone conformation for
the epimeric analogues relative to their respective natural product
counterparts. These structural differences could, in turn, enhance
or diminish the ability of these epimeric compounds to
participate in noncovalent and covalent binding in the minor
groove of DNA.13
other protecting groups present. Additionally, it was reasoned
that the compact size of these groups would minimize steric
shielding of the secondary amine and improve the reactivity of
compound 25 for coupling with compound 19.
With straightforward access to compounds 19 and 25 bearing
the appropriate features necessary for the convergent peptide
coupling, the stage was set for joining the eastern and western
halves of 1 and 2. Amino acid 19 was initially converted into
the corresponding acid chloride by treatment with oxalyl
chloride and was then coupled to compound 25 in the presence
of 2,6-lutidine to afford the desired peptide 26 in 89% yield
(Scheme 4).
The next step entailed installation of the requisite aldehyde
group in compound 26 to produce the desired cyclization
substrate 14 (Scheme 1). Therefore, initial selective removal
of the O-TBS group at the relevant primary hydroxyl position
afforded a free alcohol intermediate, which was subsequently
converted to the corresponding aldehyde 27 through a Swern
protocol11 (oxalyl chloride, DMSO, NEt3) in excellent yield for
two steps. Cyclization of compound 27 was accomplished in a
one-pot procedure. Initial treatment of compound 27 with TBAF
simultaneously removed the phenolic O-TBS and N-Fmoc
groups, producing an iminium intermediate through collapse of
the resulting free secondary amine group onto the aldehyde
group. Subsequent treatment of this reactive intermediate in situ
with excess MsOH promoted nucleophilic attack of the electron-
rich eastern arene unit onto the electrophilic iminium species.
This reaction generated compound 28, exclusively, in 89% yield
bearing the opposite configuration at C-3 with respect to the
natural products. The structure of compound 28 was subse-
quently confirmed through single-crystal X-ray analysis (Figure
2).
With these thoughts in mind, we turned our attention toward
the conversion of compound 28 to the C-3-epi variants of
compounds 1 and 2, 3-epi-jorumycin (32) and 3-epi-reniera-
mycin G (34), respectively. The synthesis of 3-epi-jorumycin
(32) commenced with conversion of the amide group in
compound 28 to the corresponding aminonitrile (Scheme 5).
This conversion entailed initial reduction of the amide group
(LiAlH4, THF) followed by trapping of the resulting carbino-
lamine group with cyanide (aqueous KCN, AcOH) affording
the desired aminonitrile intermediate. Subsequent reductive
removal of the allyl groups from this species afforded compound
29 in 93% yield for two steps. Initial DDQ oxidation of the
The observed epimerization at C-3 was quite unexpected. On
one hand, Danishefsky and co-workers obtained a 3-epi-
pentacyclic intermediate en route to cribrostatin IV (reniera-
mycin H) through an intramolecular C3-C11 bond-forming
Mannich condensation.12 On the other hand, Corey and co-
(11) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651-1660.
(12) Chan, C.; Heid, R.; Zheng, S.; Guo, J.; Zhou, B.; Furuuchi, T.; Danishefsky,
S. J. J. Am. Chem. Soc. 2005, 127, 4596-4598.
(13) Hill, G. C.; Remers, W. A. J. Med. Chem. 1991, 34, 1990-1998.
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A R T I C L E S
Lane et al.
Scheme 5. Synthesis of 3-epi-Jorumycin (32)
Table 1. Antiproliferative Activity of 3-epi-Jorumycin (32) and
Related Synthetic Intermediatesa
cell line
compound
A549
HCT-116
29
30
31
32
>10
6.2
5.1
>10
>10
4.4
2.0
4.9
a Values reported are GI50 in µM.
Scheme 6. Synthesis of 3-epi-Renieramycin G (34)
Figure 3. Overlay of compounds 28 (red) and 41 (gray).
for two steps. Subsequent DDQ oxidation of the hydroquinone
units in compound 33 to the corresponding bis-quinone produced
3-epi-renieramycin G (34) in 66% yield.
Preliminary cytotoxicity assays were conducted on com-
pounds 29-32 to determine whether antiproliferative activity
had been retained. Compounds 29-32 were screened against
two human cancer cell lines (A549 and HCT-116) (Table 1),
and results revealed low micromolar inhibition profiles for all
compounds tested, verifying the retention of antitumor potential
for this new class of agents despite the inversion of configuration
at C-3. However, as (-)-jorumycin (1) and presumably related
intermediates are known to be unstable,2 accurate determinations
of relative cytotoxicity for the 3-epi analogues in comparison
to the parent natural products (1 and 2) would have to be
conducted simultaneously. This requirement, therefore, provided
additional motivation for the development of a viable synthetic
route to our original targets, compounds 1 and 2.
It is quite significant that the C-3-epi substances display
substantial cytotoxicity, and this was quite unexpected based
on an initial consideration of the anticipated substantial change
in geometry that the C-3-epi stereochemistry would render on
C-21, the well-accepted site of DNA alkylation within the
saframycin-ecteinascidin family of antitumor agents.1 To gain
some preliminary insight into the C-3-epi series, we have
compared the geometry of compound 28 as revealed through
X-ray analysis with the energy minimized geometry of 41 (vide
infra) as shown in the overlay presented in Figure 3. While these
are both amide-containing substrates, the overall spatial ar-
rangements of the C-21 carbon atom in both substrates are found
in a surprisingly similar region of space when the left-hand A-B
ring systems are overlapped. This preliminary modeling exercise
provides the reasonable expectation that the C-3-epi compounds,
such as 30 and 31, should be functionally capable of alkylating
the exocyclic amine group of guanine residues in the minor
groove of DNA in a fashion similar to that established for the
hydroquinone units in compound 29 afforded bis-quinone 30
in 46% yield. The primary hydroxyl group in compound 30
was then acylated to give compound 31 in 78% yield. Treatment
of compound 31 with aqueous AgNO3 cleanly afforded 3-epi-
jorumycin (32) in 80% yield. The relative configurations at the
aminonitrile and carbinolamine positions (C-21) of compounds
30 and 32, respectively, were verified through 1H NMR coupling
constant analysis.14
With our first epimeric target in hand, efforts were then
directed toward the conversion of compound 28 to 3-epi-
renieramycin G (34). Thus, initial removal of the allyl groups
in compound 28 afforded a triol intermediate (Scheme 6).
Selective acylation of the primary alcohol group in this
intermediate with angelic acid was accomplished under modified
Yamaguchi conditions15 to afford compound 33 in 78% yield
(14) 2D NOe analyses of compounds 29-32 were inconclusive in regards to
establishing the respective configurations at C-21. However, the coupling
constants (J’s) between H-21 and H-13 were successfully measured for
compounds 30 and 32 at 1.9 and 2.1 Hz, respectively. Based on dihedral
angles derived from energy-minimized structures of 30 and 32 bearing both
possible configurations at C-21, these J’s were consistent with the respective
assigned stereochemistries at this position.
(15) Hartmann, B.; Kanazawa, A. M.; Depres, J.-P.; Green, A. E. Tetrahedron
Lett. 1991, 32, 5077-5080.
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Asymmetric Total Synthesis of (−)-Jorumycin
A R T I C L E S
Scheme 7. Cyclization Studies on Alternate Substrates 35, 36
Scheme 8. Synthesis of Pentacycle 41
natural products.1 Efforts to explore the biochemical reactivity
of these compounds are presently under study and will be the
subject of a separate disclosure.
Access to the natural substances 1 and 2 required a method
for the synthesis of a versatile pentacyclic intermediate (15)
bearing the natural configuration at C-3. To achieve this goal,
a thorough investigation was conducted to determine a viable
route to obviate the undesired epimerization at C-3. The
cyclization of our original substrate, compound 27, was initially
conducted under basic conditions (TBAF) followed by treatment
of the incipient iminium intermediate with excess acid (MsOH).
Therefore, it was initially conjectured that perhaps the epimer-
ization was mediated by base. This postulate seemed reasonable
based on previous reports by Corey and co-workers of similar
cyclizations whereby iminium formation and subsequent cy-
clization were both conducted under acidic conditions to
successfully afford compounds bearing the natural configuration
at C-3.9a,b
To test our theory, a cyclization substrate bearing acid-labile
protecting groups at the relevant positions was desired. This
new protection strategy would also permit access to a C-3-epi
cyclization substrate through deliberate base-mediated equilibra-
tion at the C-3 aldehyde position (renieramycin numbering).
The epimeric substrate would serve to determine the depen-
dence, if any, of the initial configuration at C-3 on the
stereochemical outcome of the cyclization. In accord with this
strategy, compound 35, bearing Boc protection at the nitrogen
and phenol positions, was synthesized by straightforward
methods from peptide 26.16 Subsequent treatment of compound
35 with DBU effectively equilibrated the configuration at C-3,
affording a diastereomeric mixture of 35 and 36 (dr ∼1:1,
Scheme 7). Subjection of compounds 35 and 36, individually,
to TFA afforded exclusively, the 3-epi pentacycle 28, which is
consistent with the behavior of compound 27 (Scheme 4).
These studies on compounds 35 and 36 confirmed that the
stereochemical outcome of the cyclization at C-3 under these
conditions was independent of the initial substrate configuration
at C-3, and, importantly, this confirmed that the epimerization
was pervasive even in the absence of base. Guided by these
preliminary findings, extensive studies were then conducted to
determine the appropriate cyclization substrate and reaction
conditions necessary to maintain the desired configuration at
the C-3 position. These efforts ultimately led to the discovery
of compound 40, a modified substrate lacking a methyl group
at the nitrogen position and bearing a free phenol group on the
eastern arene unit.
Preparation of compound 40 proved straightforward and
commenced with the coupling of modified amino acid 37,17
through its corresponding acid chloride, to compound 25 in the
presence of 2,6-lutidine to afford the desired peptide 38 in 93%
yield (Scheme 8). The N-Fmoc group in compound 38 was then
removed with piperidine, and the resulting free amine was
reprotected as the corresponding Boc carbamate to afford the
desired intermediate. Selective removal of the O-TBS protecting
group at the primary hydroxyl position in this intermediate was
accomplished under acidic conditions producing alcohol 39 in
84% yield for three steps. Subsequent oxidation of the primary
hydroxyl group in 39 to the corresponding aldehyde through
the agency of the Dess-Martin reagent18 resulted in a hemi-
aminal intermediate. Removal of the phenolic O-TBS group in
the intermediate produced compound 40 as a single diastereomer
(hemi-aminal configuration established by 2D ROESY NMR)
in 92% yield for two steps. Gratifyingly, subjection of substrate
40 to TFA afforded a pentacyclic compound in high yield
bearing the desired natural configuration at C-3. Installation of
the N-Me group in this intermediate through reductive amination
with formaldehyde produced compound 41 in 71% yield for
two steps, appropriately endowed for conversion to the natural
alkaloids.
The modified cyclization strategy proceeding through com-
pound 40 was somewhat less convergent than our previous route
to 3-epi-pentacycle 28 due to necessary protecting group
manipulations and a late-stage installation of the requisite N-Me
group. Nonetheless, the specific structural features of compound
(16) Compound 35 was prepared from peptide 26 through the following
sequence: (1) TBAF, THF, room temperature; then excess Boc2O; (2)
Boc2O, EtOH, room temperature; (3) Dess-Martin [O].
(17) Compound 37 was prepared from amine 17 in two steps: (1) PdCl2, EtOH,
H2; (2) FmocOSu, aqueous NaHCO3, CH2Cl2 (see Supporting Information).
(18) Dess, B. D.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
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A R T I C L E S
Lane et al.
Scheme 9. Synthesis of (-)-Jorumycin (1)
Scheme 10. Synthesis of (-)-Renieramycin G (2)
40 were found to be crucial to the success of the cyclization.
Indeed, any attempts to cyclize substrates incorporating an acid
labile group at the eastern phenolic position or an N-Me group
resulted only in the production of 3-epi-pentacycle products in
addition to undesired byproducts.
corresponding bis-quinone produced (-)-renieramycin G (2) in
63% yield (Scheme 10). The synthetic (-)-renieramycin G had
spectral data fully consistent with those previously reported for
the natural substance.5,19
With compound 41 in hand, we initially endeavored to
complete the synthesis of (-)-jorumycin (1). In accord with
the route to 3-epi-jorumycin (32), conversion of the amide group
in compound 41 to the corresponding aminonitrile proceeded
as before (LiAlH4, THF, then aqueous KCN, AcOH). Subse-
quent reductive removal of the allyl groups in this intermediate
afforded the corresponding triol. Oxidation of the hydroquinone
units in the triol intermediate afforded the bis-quinone 42 in
49% yield for three steps. Importantly, spectroscopic data from
compound 42 matched data from the same intermediate reported
previously by Saito and co-workers in their semisynthesis of
(-)-jorumycin (1) from renieramycin M (4).4 The primary
hydroxyl group in compound 42 was then acylated to give an
acetate intermediate, after which treatment of this intermediate
with aqueous silver nitrate cleanly afforded (-)-jorumycin (1)
in 78% yield for two steps (Scheme 9). The synthetic jorumycin
had spectral data consistent with that previously reported for
the natural substance2 and for the material derived through
semisynthetic methods.4
Consistent with our route to 3-epi-renieramycin G (34),
conversion of compound 41 to (-)-renieramycin G (2) proved
straightforward. Initial removal of the O-allyl groups from
compound 41 afforded a triol intermediate, which was subjected
to selective acylation of the primary alcohol group with angelic
acid under modified Yamaguchi conditions15 as above, to afford
compound 43 in 66% yield for two steps. Subsequent DDQ
oxidation of the hydroquinone units in compound 43 to the
Conclusion
The asymmetric total syntheses of (-)-jorumycin (1) and (-)-
renieramycin G (2) have been accomplished in 25 and 23 steps,
respectively. Additionally, 3-epi-jorumycin (32) and 3-epi-
renieramycin G (34) were also successfully synthesized, the
former of which, including related synthetic intermediates,
displayed significant cytotoxicity in preliminary biological
evaluation. Efforts to utilize this approach for the concise
asymmetric synthesis of other members of the renieramycin
family, the ecteinascidins, saframycins, as well as the safracins
and some mechanistically inspired analogues, including epimers,
are currently under study in our laboratories.
Acknowledgment. We thank the National Institutes of Health
for financial support (Grant CA85419) and the NIH National
Cancer Institute for postdoctoral fellowship support for J.W.L.
(Grant CA105898). We are indebted to Dr. Jeff Spencer, Peter
Sabbatini, and Jason Oeh of Celera-SSF for kindly providing
the cytotoxicity data for compounds 29-32. We thank Prof.
Angelo Fontana (Istituto di Chimica Biomolecolare (ICB) del
CNR, Italy) for providing spectral data for (-)-jorumycin. We
are grateful to Professor Phil Magnus of the University of Texas,
Austin, for sending us a preprint of their manuscript describing
the synthesis of (()-renieramycin G (see accompanying com-
munication in this issue, http://dx.doi.org/10.1021/ja0535817).
Supporting Information Available: Complete experimental
and spectroscopic data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(19) We were unable to acquire an authentic specimen of natural renieramycin
G from Prof. B. S. Davidson (ref 5) with which to compare our synthetic
sample. The isolation paper (ref 5) notes that the natural product was
unstable. Furthermore, an optical rotation for this natural product has
heretofore not been recorded.
JA0535918
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12690 J. AM. CHEM. SOC. VOL. 127, NO. 36, 2005