A synthesis of the tricyclic core structure of FR901483 featuring an Ugi four-component coupling and a remarkably selective elimination reaction

Article abstract of DOI:10.1055/s-2008-1042813

Three key reactions, an efficient Ugi four-component coupling, a regiospecific, base-mediated elimination reaction, and an intramolecular nitrone/alkene [3+2] cycloaddition, were used to achieve an effective synthesis of the tricyclic molecular framework of the immunosuppressant FR901483. The outcome of a control experiment supports the idea that an internal deprotonation by an alkoxide ion is the origin of the site selectivity observed in the base-induced elimination of hydroxy mesylate 17. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042813

LETTER
695
A Synthesis of the Tricyclic Core Structure of FR901483 Featuring an Ugi
Four-Component Coupling and a Remarkably Selective Elimination Reaction1
Synthesis of the
Ti
r
Core Str
o
ucture of FR
f
901483umi Seike, Erik J. Sorensen*
Frick Chemical Laboratory, Princeton University, Princeton, NJ 08544-1009, USA
Fax +1(609)2581980; E-mail: ejs@princeton.edu
Received 8 October 2007
This paper is dedicated to the pioneering achievements of Professor Yoshito Kishi in the field of organic chemistry on the occasion of his
70th birthday.
the field of chemical synthesis. Five laboratories, includ-
Abstract: Three key reactions, an efficient Ugi four-component
ing ours, published syntheses of the full structure of this
coupling, a regiospecific, base-mediated elimination reaction, and
an intramolecular nitrone/alkene [3+2] cycloaddition, were used to
achieve an effective synthesis of the tricyclic molecular framework
natural product.3–7 In addition to these achievements, sev-
eral laboratories described either formal syntheses of
of the immunosuppressant FR901483. The outcome of a control ex- FR901483 or novel concepts for constructing its rigid,
azatricyclic core structure.8 In 2000, our laboratory de-
periment supports the idea that an internal deprotonation by an
alkoxide ion is the origin of the site selectivity observed in the base-
induced elimination of hydroxy mesylate 17.
scribed an enantiospecific, nature-inspired synthesis of
this natural product from two simple tyrosine derivatives
featuring the following key transformations: a C–N bond-
forming oxidative dearomatization, an aldol cyclization,
Key words: Ugi four-component coupling, elimination reaction,
[3+2] cycloaddition
and a late-stage Mitsunobu substitution that simulta-
neously produced the phosphate ester of 1 and the desired
stereochemistry at C-9.4 While the brevity of this design
for synthesis was attractive, we were not entirely satisfied
with the yields of these three transformations or with the
level of selectivity (both regio- and diastereoselectivity)
for the aldol cyclization step. This circumstance engen-
dered a new way of thinking about the problem of gaining
a rapid access to the azaspirotricyclic core structure of
FR901483. The general features of this alternative synthe-
sis are outlined below in Scheme 1.
Scientists from the Fujisawa Pharmaceutical Company
isolated the natural product FR901483 (1) from the fer-
mentation broth of the fungus Cladobotryum sp. No.
11231 in the course of a search for new immunosuppres-
sive agents with mechanisms of action different from cy-
closporine A and FK-506.2 The unique and rigid
molecular architecture of 1 (Figure 1), which seems to
conceal most of the atoms of two molecules of tyrosine,
was revealed by an X-ray crystallographic analysis. The
phosphate ester is another interesting element of this sub-
stance that is essential to its potent immunosuppressive
activity in vitro. FR901483 significantly extends graft sur-
vival time in the rat skin allograft model and is believed to
exert its immunosuppressive function by inhibiting purine
nucleotide biosynthesis.
The idea that compounds 2–5 would join spontaneously
by the Ugi coupling process9 to give compound 6 was a
key aspect of this design. If it succeeded, this union would
produce a polyfunctional compound having the crowded
C–N bond and all of the carbon atoms found in the tricy-
clic core structure of FR901483 from four simple com-
pounds. Indeed, amine 2 and Armstrong’s cyclohexenyl
isocyanide 510 can be readily prepared, while the
monoketal of 1,4-cyclohexandione 3 and acetic acid (4)
are commercially available. In the wake of converting the
enamide moiety in 6 to an ester (or a thioester), we would
then be in a position to generate the C2–C3 bond in com-
pound 7 via a Dieckmann condensation.11 A few seeming-
ly straightforward functional group manipulations and an
alkene synthesis, which would have to be selective, could
then afford alkenyl aldehyde 8. While the alkene in 8 is
disubstituted and not especially electron-rich, the p-elec-
trons of this group would enable the desired ring forma-
tion if a Prins cyclization12 could be achieved. In essence,
this would involve a trans addition of an activated alde-
hyde carbonyl carbon and an external nucleophile to the
disubstituted alkene in 8. By far the most attractive mani-
festation of this idea would be a direct conversion of 8 into
9 by a Prins cyclization in which the trapping nucleophile
is a simple phosphate ion. To the best of our knowledge,
The status of 1 as a potential immunosuppressant and its
attractive structure stimulated much creative research in
OMe
Me
H
H
N
HO
H
N
H
OH
OH
H
O
P
O
1: FR901483
Figure 1 The molecular structure of FR901483 (1)
SYNLETT 2008, No. 5, pp 0695–0701
x
x.
x
x.
2
0
0
8
Advanced online publication: 26.02.2008
DOI: 10.1055/s-2008-1042813; Art ID: S08007ST
© Georg Thieme Verlag Stuttgart · New York

696
H. Seike, E. J. Sorensen
LETTER
BnO
NH2
OMe
OMe
OMe
OR
O
2
O
O
Ugi coupling
OBn
OR
OBn
OR
OR
Me
N
N
H
N
3
NC
O
2
O
5
3
O
Me
OH
OR
OR
4: acetic acid
6
7
OMe
OMe
Prins cyclization
with incorporation
of phosphate?
O
O
4
H
N
H
3
N
CHO
HO
7
H
8
9
OR
OR
O
P
9
8
O
Nu
Scheme 1 A strategy for constructing the azatricyclic architecture of FR901483 from four simple starting materials
OMe
O
OBn
Me
N
H
N
MeOH, r.t.
(62–93% yield)
O
BnO
O
O
NH2
OMe
6
Ugi coupling
O
2
O
AcCl (5 equiv),
MeOH, r.t.
(90% yield)
NC
O
MeOH, r.t.; then
MeOH, AcCl (5 equiv),
r.t. (66% yield)
O
5
3
OMe
Me
OH
4: acetic acid
O
OBn
OMe
Me
N
MeO
O
OMe
10
Scheme 2 The Ugi reaction enables direct syntheses of compounds 6 and 10
Prins reactions with incorporation of phosphate are not plete with useful functionality, in yields ranging from 62–
found in the literature. Nevertheless, we were drawn to the 93% (Scheme 2). Exposure of enamide 6 to anhydrous
potential of 8 as a useful intermediate in our synthesis and HCl in methanol, generated by methanolysis of acetyl
confident that we would identify a reaction suitable for chloride, gave rise to compound 10 via methyl ester for-
forming the needed ring.
mation and concomitant 1,3-dioxolane–dimethyl ketal ex-
change. In fact, it was possible to directly form 10 in one
pot simply by adding methanol and acetyl chloride to the
Ugi product generated by the union of compounds 2–5 in
methanol. This single laboratory operation effectively as-
sembles a structure with a proper placement of carbon at-
oms and the needed nitrogen atom for a synthesis of the
tricyclic core framework of FR901483. Moreover, this
Within the family of multicomponent coupling reactions,
the Ugi reaction is unique in its ability to rapidly produce
complex molecular structures from four simple inputs and
broad applicability to problems in chemical synthesis.13
To our delight, a simple mixing of Armstrong’s isocya-
nide 510 with compounds 2, 3, and 4 in methanol at room
temperature resulted in the formation of 6, a compound re-
Synlett 2008, No. 5, 695–701 © Thieme Stuttgart · New York

LETTER
Synthesis of the Tricyclic Core Structure of FR901483
697
Scheme 3 Synthesis of key intermediate 17
process generates a chirotopic, nonstereogenic center14 the ketal protecting group gave rise to keto lactam 13. The
and thus is not complicated by the production of diaste- five-step sequence starting from the Ugi product 10 did
reoisomers.
not require any chromatographic purifications and pro-
duced keto lactam 13 in 73% overall yield with an average
yield of 94% for each step.
We were pleased with our direct synthesis of compound
10 and could, from this vantage point, make rapid
progress toward the larger objective. To this end, deproto- From the outset, we were aware that the advantage gained
nation of the acetamide in 10 with potassium tert-butoxide by using the simple, symmetrical, and commercially
in THF at 0 °C triggered an efficient Dieckmann available ketone 3 in the Ugi construction of 10 would
cyclization11 to a b-keto amide (i.e. compound 7, evaporate if we could not achieve a selective placement of
R = Me), which was subsequently reduced with sodium the alkene into the six-membered ring on the path to key
borohydride to the epimeric mixture of secondary alco- intermediate 8 (Scheme 1). Of course, there are some pop-
hols shown as 11. To remove the unneeded hydroxyl ular methods to transform ketones into alkenes, but it was
group, ethyl acetate was added to the potassium alkoxide unclear how any of these would enable us to generate the
salts formed by deprotonating the epimeric mixture of al- desired alkene in a selective fashion. This nontrivial selec-
cohols by potassium tert-butoxide; this action resulted in tivity problem stimulated the intriguing idea that meth-
a rapid and efficient formation of a,b-unsaturated lactam anesulfonate ester 17 might, under basic conditions,
12. This simple procedure, which presumably involves an undergo the desired elimination with acceptable margins
in situ formation and subsequent elimination of acetate es- of selectivity. This idea followed from two assumptions
ters, was developed by Funk and co-workers.6 After hy- (Figure 2). First, we surmised that a minimization of both
drogenation of the newly formed alkene over Adams’s steric repulsion between the cyclohexane ring and the side
catalyst, a straightforward, acid-catalyzed hydrolysis of chains on C6 and destabilizing allylic strain might hinder
Synlett 2008, No. 5, 695–701 © Thieme Stuttgart · New York

698
H. Seike, E. J. Sorensen
LETTER
OMe
O
OMe
MeO
O
H
O
HO
H
O
OH
6
N
H
H
H
H
H
H
Ca
Ca
Cb
Cb
Me
O
O
O
S
OSO2Me
Newman projection A
OSO2Me
Newman projection B
18
Figure 2 A concept for achieving a selective alkene synthesis
O
1. trans-diaxial
elimination
OH
H
O
O
Br
Br
Br
O
O
O
O
O
O
SN2'
K2CO3, DMF
H
2. K2CO3
H
H
O
Br
H
Br
H
O
19
20
Welch et al.16
anti-periplanar
elimination
t-BuOK,
t-BuOH,
Br
20 d
no reaction
+
53 °C,
< 1 h
Br
Br
H
H
HO
O
HO
O
H
21
22
Menger et al.17
Scheme 4 Two examples of eliminations by internal bases
rotation about the N–C6 bond. If this were so, then the hy- To set the stage for the pivotal elimination reaction, ke-
droxyl function of 17 would be hovering over only one of tone 13 was reduced with sodium borohydride to a 12:1
the axial C–H bonds with an antiperiplanar relationship15 mixture of epimeric alcohols 14 and 15 favoring the de-
to the mesylate leaving group (see Newman projection B); sired equatorial alcohol diastereoisomer 15 (Scheme 3).
the assumption here was that Newman projection B might Treatment of this compound with methanesulfonyl chlo-
be a close approximation of the reactive conformation ride and Hünig’s base gave rise to methane sulfonate ester
through which the elimination reaction would take place. 16 in 96% yield. A high-yielding hydrogenolysis of the
Second, we assumed that a suitably strong base would benzyl ether in 16 afforded the crystalline hydroxy mesy-
deprotonate the free hydroxyl group in 17 and that the re- late 17. In the solid state, compound 17 is a close, chair-
sulting alkoxide ion would be well-positioned to attack flipped conformational relative of the Newman projec-
the axial Ca–H bond, thus triggering the formation of the tions shown in Figure 2. Interestingly, while benzyl ether
desired alkene via an intramolecular, anti elimination of mesylate 16 was recovered unchanged after exposure to
methanesulfonate (see arrows in 18).
five equivalents of potassium tert-butoxide in tert-butyl
alcohol at 80 °C for two hours, exposure of hydroxy me-
sylate 17 to the same conditions for one hour resulted in
the formation of a single cyclic alkene 23 in 97% yield
(Scheme 5). Excellent yields of alkene 23 were also ob-
tained by exposure of hydroxy mesylate 17 to sodium hy-
dride in DMF, although THF was unsuitable as a reaction
solvent. The observation that benzyl ether mesylate 16 is
impervious to the action of the same bases that cause a
smooth and regiospecific alkene synthesis from alcohol
17 is consistent with our prediction that a C7 alkoxide ion
is serving the role of internal base in an anti elimination of
The carboxylate ion- and alkoxide ion-initiated anti elim-
inations of HBr published by the laboratories of Welch16
and Menger,17 respectively (19 → 20, 21 → 22,
Scheme 4), are instructive examples where advantage was
taken of an ‘internal base’ to bring about efficient elimi-
nation behavior.18 If it succeeded in the context of alcohol
mesylate 17, this type of proximity-dependent tactic
would provide a simple solution to the challenging prob-
lem of generating the desired cyclohexene.
Synlett 2008, No. 5, 695–701 © Thieme Stuttgart · New York

LETTER
Synthesis of the Tricyclic Core Structure of FR901483
699
OMe
t-BuOK (5 equiv),
no reaction
OBn
H
t-BuOH, 80 °C, 2 h
O
O
S
O
Me
N
O
16
OMe
O
OMe
OMe
O
conditions
O
H
OH
OH
H
H
H
O
O
N
S
O
Me
N
O
OSO2Me
17
23
Conditions
Yield of 23
5 equiv t-BuOK, t-BuOH, 80 °C, 1 h
5 equiv NaH, DMF, 40 °C, 4 h
5 x 3 equiv NaH, DMF, r.t., 48 h
3 equiv NaH, THF, r.t., 12 h
97%
93%
98%
no reaction
Scheme 5 A regiospecific, base-mediated elimination of hydroxy mesylate 17
the secondary mesylate. Analysis of the elimination ex- gave only unreacted starting material and no evidence of
periments conducted with compound 17 by 400 MHz a productive nitrile oxide/alkene cycloaddition. By con-
NMR before purification clearly indicated that only one trast, nitrone 24, produced by the condensation of N-ben-
alkene product was formed. However, owing to the sym- zylhydroxyl amine with aldehyde 8, demonstrated useful
metrical nature of the newly formed cyclohexene, we reactivity. When a solution of this compound in toluene
were unable to make a confident structural assignment by was heated to 130 °C for 18 hours, the desired nitrone/alk-
NMR and tentatively assigned the structure of the alkene ene [3+2] dipolar cycloaddition took place and afforded
product as 23 based on our supposition that alcohol mesy- isoxazolidine 25 in 80% yield. The structure of compound
late 17 would eliminate in a selective fashion. The out- 25 was supported by extensive NMR analysis, including
come of a transformation described below ultimately H–H COSY, C–H HMQC, and NOESY techniques. It
proved that compound 23 does indeed have the structure was also possible to reduce the N–O bond of 25 by the ac-
shown.
tion of zinc powder in a warm (60 °C) solvent mixture of
AcOH–THF–H2O to reveal 26, a compound embodying
the tricyclic core structure of FR901483. This substance
gave a crystal suitable for X-ray crystal structural analy-
sis, which unambiguously confirmed its structure and, in-
cidentally, the regiochemical course of the pivotal
elimination step shown in Scheme 5.
With an effective solution to the problem of generating
the desired cyclohexene, attention was turned to the test-
ing of the tandem vicinal difunctionalization strategy out-
lined in Scheme 1. An oxidation of alcohol 23 with the
Dess–Martin periodinane did accomplish the formation of
the desired alkenyl aldehyde 8 (Scheme 6). However, all
attempts to achieve Prins cyclizations with incorporation The primary aim of this project, namely the development
of heteroatom nucleophiles at C9 were unsuccessful, pre- of a rapid synthesis of the type of topology found in the
sumably due to the unreactive nature of the disubstituted potent immunosuppressive natural product FR901483 (1),
ring alkene; these experiments led only to a recovery of was achieved. An Ugi coupling of four simple com-
unreacted alkenyl aldehyde 8.19 Efforts to achieve an in- pounds, two of which are commercially available, gave
tramolecular Paterno–Büchi photocycloaddition and a sa- direct access to the fully substituted, nitrogen-bearing car-
marium diiodide mediated, reductive aldehyde/alkene bon and a structure having all of the required carbons.
cyclization with compound 8 also did not produce the de- This process, the intramolecular elimination that generat-
sired products.
ed the desired alkene in a regiospecific fashion, and a
[3+2] dipolar cycloaddition reaction were the main trans-
formations. Our most advanced FR-like tricycle, com-
pound 26, was not converted to the natural product that
inspired this effort. However, it is quite likely that the
chemistry described here could be adapted to concise syn-
theses of even closer structural relatives of FR901483.
In the wake of these experiments, the decision was made
to explore the feasibility of intramolecular [3+2] dipolar
cycloaddition reactions. To this end, the aldehyde func-
tion of 8 was efficiently converted to the corresponding
oxime; however, efforts to oxidize the oxime to a nitrile
oxide with either sodium hypochlorite or chloramine T
Synlett 2008, No. 5, 695–701 © Thieme Stuttgart · New York

700
H. Seike, E. J. Sorensen
LETTER
Scheme 6 Completion of tricyclic carbon skeleton of FR901483
(8) (a) Yamazaki, N.; Suzuki, H.; Kibayashi, C. J. Org. Chem.
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Acknowledgment
This work was supported by the Skaggs Institute for Chemical Bio-
logy, The Scripps Research Institute (TSRI), the National Institute
of General Medical Sciences (GM065483), the 2001 AstraZeneca
Award for Excellence in Organic Chemistry (EJS), and the Merck
Research Laboratories. A predoctoral fellowship from the Heiwa
Nakajima Foundation to H.S. is also gratefully acknowledged. We
sincerely thank Professor K. C. Nicolaou for generously providing
laboratory space and facilities to H.S. during the period of Septem-
ber, 2003 to January, 2004. We also thank Dr. Raj Chadha (TSRI)
for the X-ray crystal structural determinations, Dr. L. B. Pasternack
and Dr. D. H. Huang (TSRI) for NMR spectroscopic assistance, and
Dr. G. Siuzdak (TSRI) for mass spectrometric assistance.
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References and Notes
(1) This manuscript is based on Chapter 2 of the Ph.D. thesis of
Hirofumi Seike, The Scripps Research Institute, 2003.
Experimental procedures and characterization data for the
new compounds described in this manuscript are available
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Synthesis of the Tricyclic Core Structure of FR901483
701
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phosphoric acids was also unsuccessful.
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