Catalytic, Asymmetric Synthesis of the C1′-C10′ Segment of Pamamycin 621A

Article abstract of DOI:10.1021/ol005714t

(Equation Presented) This paper describes a catalytic, asymmetric approach to the C_1′-C_10′ segment of pamamycin 621A. We synthesize this segment in a convergent manner, with each of the coupling partners ultimately deriving from enantiomerically enriched methylketene dimer.

Full text of DOI:10.1021/ol005714t

ORGANIC
LETTERS
2000
Vol. 2, No. 11
1529-1531
Catalytic, Asymmetric Synthesis of the
C −C Segment of Pamamycin 621A
1′
10′
,†
Michael A. Calter* and F. Christopher Bi
Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24061-0212
calter@chem.rochester.edu
Received February 23, 2000
ABSTRACT
This paper describes a catalytic, asymmetric approach to the C −C10′ segment of pamamycin 621A. We synthesize this segment in a convergent
1′
manner, with each of the coupling partners ultimately deriving from enantiomerically enriched methylketene dimer.
The pamamycins, a family of closely homologous macro-
cycles, exhibit antibacterial and antifungal activity. The
supply of pamamycins from natural sources is limited, and
these molecules occur as a complex, hard-to-separate mixture
of the homologues (Figure 1).1
reactions of the current approaches to the pamamycins make
them unattractive for producing the amounts of compounds
necessary for clinical testing. We have developed an alternate
synthesis to a portion of pamamycin 621A that requires
relatively few steps and employs methylketene dimer 1,
available from asymmetric catalysis, as the ultimate source
of all the chiral centers in the target (Scheme 1).3 Addition-
ally, this synthesis promises to be flexible enough to assemble
both the C1′-C8′ and C1-C8 fragments by the same basic
method.
Scheme 1
Figure 1. Pamamycin 621A.
Although the antibiotic activity of the pamamycins has
made them popular targets for total synthesis, no groups have
synthesized any member of the pamamycin family.2 Fur-
thermore, the length and the reliance on auxiliary-controlled
† Current address: Department of Chemistry, University of Rochester,
Rochester, NY 14627-0216.
(1) Kondo, S.; Yasui, K.; Natsume, M. Katayama, M.; Marumo, S. J.
Antibiot. 1991, 32, 3087-3090.
(2) (a) Walkup, R. D.; Kim, Y. S. Tetrahedron Lett. 1995, 36, 3091-
3094. (b) Marvopoulos, I.; Perlmutter, P. Tetrahedron Lett. 1996, 37, 3751-
3754. (c) Mandville, G.; Bloch, R. Eur. J. Org. Chem. 1999, 2303-2307.
(d) Solladie´, G.; Salom-Roig, X. J.; Hanquet, G. Tetrahedron Lett. 2000,
41, 551-554.
10.1021/ol005714t CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/29/2000

We chose to demonstrate our method by synthesizing 2,
which corresponds to the C1′-C10′ segment of pamamycin
621A. Although 2 does not contain C11′ and therefore does
not comprise a complete synthon for the bottom half of
pamamycin, a minor modification of the sequence should
afford the complete bottom half synthon. Our route to 2
passes through R,â-unsaturated ketone 3 and â-hydroxyamide
4. Both of these intermediates are available in a very rapid
and convenient manner from bromopropionyl bromide.
The preparation of 3 began with the addition of the lithium
amide derived from N,O-dimethylhydroxylamine (produced
by the reaction of the amine with n-butyllithium) to methyl-
ketene dimer 1, followed by in situ trapping of the resulting
lithium enolate to afford a trimethylsilyl enol ether (Scheme
2). The instability of this compound caused us to use it
To couple the two portions of the segment, we decided to
convert C6′ of 4 into a nucleophilic center in preparation for
addition to the electrophilic C5′ of 3. To accomplish this
switch, we first protected the C8′-hydroxyl and then reduced
the Weinreb amide to form aldehyde 5 (Scheme 4).7 Addition
Scheme 4
Scheme 2
of tributylstannyllithium to 5, followed by protection, gave
a 3:1 mixture of R-alkoxystannanes in low yield.8 The major
diastereomer is that predicted by the Felkin-Anh model.9,10
However, this reaction appeared to be under partial thermo-
dynamic control, as variation of the reaction time resulted
in a variation of the diastereomeric ratio of the products.11
We had intended to use the major diastereomer, 6, as a
precursor for a cuprate reagent to add to 3. However,
attempted transmetalation of 6 resulted in complete transfer
of the TBS group from oxygen to carbon.
without purification in the subsequent oxidation step. The
optimal conditions we found for the oxidation of the silyl
ether were the use of a stoichiometric amount of Pd(II), to
give 3 in 40% overall yield from bromopropionyl bromide.4
The low overall yield of 3 and the use of stoichiometric
palladium were obvious drawbacks to this route, and we are
exploring alternate conditions for the oxidation. Also note
that a potential route to the homologous equivalent of 4
necessary for the synthesis of the complete C1′-C11′ segment
could start with 3 and proceed via conjugate addition of a
methyl anion equivalent followed by ketone reduction.
Our route to 4 started with opening 1 with N,O-dimethyl-
hydroxylamine itself to yield a â-ketoamide (Scheme 3).5
This â-ketoamide was reduced in situ with KB(Et)3H to yield
anti-â-hydroxyamide 4 with high diastereo- and enantio-
selectivity.6
To preclude the possibility of silyl migration, we converted
the C8′-hydroxyl protecting group from silyl ether to PMB
ether (Scheme 5). Synthesis of 9 using this method afforded
Scheme 5
Scheme 3
higher overall yields than an alternative method involving
installation of the PMB protecting group prior to stannate
addition.
(3) Calter, M. A. J. Org. Chem. 1996, 61, 8006-8007.
(4) Mehta, G.; Murthy, A. N.; Reddy, D. S.; Reddy, A. V. J. Am. Chem.
Soc. 1986, 108, 3443-3452.
(5) Calter, M. A.; Guo, X. J. Org. Chem. 1998, 63, 5308-5309.
(6) Ito, Y.; Katsuki, T.; Yamaguchi, M. Tetrahedron Lett. 1985, 26,
4643-4646.
(7) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-3818.
(8) Still, W. C. J. Am. Chem. Soc. 1978, 100, 1481-1487.
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Org. Lett., Vol. 2, No. 11, 2000

We coupled 3 and 9 by first transmetallating 9 to a form
a mixed, higher order cuprate and then adding the cuprate
to 3 to yield 10 (Scheme 6).12 Reduction of 10 under
However, treatment of 11 with HCl in MeOH cleanly
removed both the PMB and MOM groups (Scheme 7).13
Scheme 7
Scheme 6
Cyclization of the resulting diol with NaH was highly
selective for the desired five-membered ring, affording the
desired C1′-C10′ segment, 2, in excellent yield.14
In summary, we have developed a convergent, catalytic,
asymmetric approach to the C1′-C10′ segment of pamamycin
621A. Furthermore, this method should also be amenable to
the synthesis of the C1-C9 segment of the pamamycins. For
example, use of the enantiomer of 1, combined with syn
selective reduction following coupling, should yield the
diastereomer necessary for the synthesis of the C1-C9
segment of pamamycin 621A.
conditions selective for the anti alcohol,5 followed by
mesylation, yielded 11. At this point, it was necessary to
remove the MOM ether from the C6′-hydroxyl. However,
this deprotection was hampered by the unexpected lability
of the PMB group on the C8′-hydroxyl. For example,
treatment of 11 with TFA resulted in initial loss of the PMB
group, followed by formal formation.
Acknowledgment. The authors wish to thank the Na-
tional Institutes of Health (R29 AI42042) and the Virginia
Tech Chemistry Department for financial support of this
project.
(9) (a) Che´rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199-2204. (b) Anh, N. T.; Eisenstein, O. NouV. J. Chem. 1977, 1, 61-
70.
(10) The stereochemistry of the addition products was proven by 1H NMR
analysis of the formals formed from 8 and its diastereomer by treatment
with TFA.
OL005714T
(11) For evidence of thermodynamic control in stannate addition, see:
Sawyer, J. S.; Macdonald, T. L.; McGarvey, G. J. J. Am. Chem. Soc. 1984,
106, 3376-3377.
(12) Linderman, R. J.; Godfrey, A.; Horne, K. Tetrahedron Lett. 1987,
28, 3911-3914.
(13) Marshall, J. A.; Palovich, M. R. J. Org. Chem. 1998, 63, 3701-
3705.
(14) Koert, U.; Stein, M.; Wagner, H. Leibigs Ann. 1995, 1415-1426.
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