An aldol approach to the total synthesis of pamamycin 621 A

Article abstract of DOI:10.1021/ol902290v

[Chemical Equation Presented] Pamamycin 621A was synthesized through a convergent route, with the THF rings constructed from Evans aldols in the presence of the chiral auxiliaries without suffering racemization or elimination. The basic amino group was in

Full text of DOI:10.1021/ol902290v

ORGANIC
LETTERS
2009
Vol. 11, No. 24
5638-5641
An Aldol Approach to the Total
Synthesis of Pamamycin 621 A
Guo-Bao Ren and Yikang Wu*
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China
yikangwu@mail.sioc.ac.cn
Received October 3, 2009
ABSTRACT
Pamamycin 621A was synthesized through a convergent route, with the THF rings constructed from Evans aldols in the presence of the chiral
auxiliaries without suffering racemization or elimination. The basic amino group was introduced at a late stage through reduction of an azido
group with n-Bu3SnH, which also demonstrates for the first time the great potential of this largely forgotten reduction protocol in synthesis
of multifunctional substrates.
Pamamycin 621A (1) is one of the 19 macrodiolide homo-
logues generated by various Streptomyces species.1 Because
of their interesting structures and bioactivities (such as
autoregulatory, anionophoric, antifungal, antibacterial activ-
ity), pamamycins have received remarkable attention from
the synthetic community since the late 1990s and conse-
quently promoted the appearance of many elegant syntheses.2
However, most studies were directed toward 607, the
simplest member in the family. Among the remainder, only
621A and 635B (Figure 1) have been synthesized to date.2g
syn-aldols generated by Evans/Crimmins aldolization4 with-
out suffering from the otherwise readily occurring side
(2) For total syntheses, see: (a) Germay, O.; Kumar, N.; Thomas, E. J.
Tetrahedron Lett. 2001, 42, 4969–4974. (b) Lee, E.; Jeong, E. J.; Kang,
E. J.; Sung, L. T.; Hong, S. K. J. Am. Chem. Soc. 2001, 123, 10131–10132.
(c) Jeong, E. J.; Kang, E. J.; Sung, L. T.; Hong, S. K.; Lee, E. J. Am.
Chem. Soc. 2002, 124, 14655–14662. (d) Wang, Y.; Bernsmann, H.; Gruner,
M.; Metz, P. Tetrahedron Lett. 2001, 42, 7801–7804. (e) Kang, S. H.; Jeong,
J. W.; Hwang, Y. S.; Lee, S. B. Angew. Chem., Int. Ed. 2002, 41, 1392–
1395. (f) Lanners, S.; Norouzi-Arasi, H.; Salom-Roig, X. J.; Hanquet, G.
Angew. Chem., Int. Ed. 2007, 46, 7086–7089. (g) Fischer, P.; Segovia,
A. B. G.; Gruner, M.; Metz, P. Angew. Chem., Int. Ed. 2005, 44, 6231–
6234. For fragment syntheses, see: (h) Walkup, R. D.; Park, G. Tetrahedron
Lett. 1988, 29, 5505–5508. (i) Walkup, R. D.; Kim, S. W.; Wagy, S. D. J.
Org. Chem. 1993, 58, 6486–6490. (j) Walkup, R. D.; Kim, S. W. J. Org.
Chem. 1994, 59, 3433–3441. (k) Walkup, R. D.; Kim, Y. S. Tetrahedron
Lett. 1995, 36, 3091–3094. (l) Mavropoulos, I.; Perlmutter, P. Tetrahedron
Lett. 1996, 37, 3751–3754. (m) Arista, L.; Gruttadauria, M.; Thomas, E. J.
Synlett 1997, 627–628. (n) Mandville, G.; Girard, C.; Bloch, R. Tetrahedron:
Asymmetry 1997, 8, 3665–3673. (o) Mandville, G.; Bloch, R. Eur. J. Org.
Chem. 1999, 2303–2307. (p) Solladie, G.; Salom-Roig, X. J.; Hanquet, G.
Tetrahedron Lett. 2000, 41, 551–554. (q) Bernsmann, H.; Hungerhoff, B.;
Fechner, R.; Frohlich, R.; Metz, P. Tetrahedron Lett. 2000, 41, 1721–1724.
(r) Calter, M. A.; Bi, F. C. Org. Lett. 2000, 2, 1529–1531. (s) Solladie, G.;
Salom-Roig, X. J.; Hanquet, G. Tetrahedron Lett. 2000, 41, 2737–2740.
(t) Bernsmann, H.; Frohlich, R.; Metz, P. Tetrahedron Lett. 2000, 41, 4347–
4351. (u) Bernsmann, H.; Gruner, M.; Metz, P. Tetrahedron Lett. 2000,
41, 7629–7633. (v) Bernsmann, H.; Gruner, M.; Frolich, R.; Metz, P.
Tetrahedron Lett. 2001, 42, 5377–5380. (w) Miura, A.; Takigawa, S.-y.;
Furuya, Y.; Yokoo, Y.; Kuwahara, S.; Kiyota, H. Eur. J. Org. Chem. 2008,
4955–4962.
A prominent structural feature present in all pamamycins
is the occurrence of three 2,5-cis-disubstituted-THF rings
incorporated into the “hidden” polyketide chains. Recently,
en route to a total synthesis of nonactin (4) we developed
an effective means3 for construction of similar rings from
(1) (a) McCann, P. A.; Pogell, B. M. J. Antibiot. 1979, 32, 673–678.
(b) Kondo, S.; Yasui, K.; Natsume, M.; Katayama, M.; Marumo, S. J.
Antibiot. 1988, 41, 1196–1204. (c) Natsume, M.; Kondo, S.; Marumo, S.
J. Chem. Soc., Chem. Commun. 1989, 1911–1913. (d) Natsume, M.; Yasui,
K.; Kondo, S.; Marumo, S. Tetrahedron Lett. 1991, 32, 3087–3090. (e)
Natsume, M.; Tazawa, J.; Yagi, K.; Abe, H.; Kondo, S.; Marumo, S. J.
Antibiot. 1995, 48, 1159–1164. (f) Natsume, M.; Honda, A.; Oshima, Y.;
Abe, H.; Kondo, S.; Tanaka, F.; Marumo, S. Biosci. Biotechnol. Biochem.
1995, 59, 1766–1768. For a recent review, see: (g) Metz, P. Top. Curr.
Chem. 2005, 244, 215–249.
10.1021/ol902290v  2009 American Chemical Society
Published on Web 11/19/2009

Scheme 1
The fragment 8 was built up from the known enal 137 via
the route shown in Scheme 2. The C-6/C-7 and C-8/C-9
Figure 1. Pamamycins 621A (1), 607 (2), 635B (3), and nonactin
(4).
reactions such as R-racemization and ꢀ-elimination caused
by the aldol carbonyl group. The ester carbonyl carbons in
the end product thus could be maintained at the same
oxidation level throughout the whole sequence without need
for recourse to otherwise unavoidable operations such as
protection, reduction, and reoxidation at these carbons. Here,
in this communication, we wish to further demonstrate the
potential of this protocol (with modification/extension)
through a novel and efficient synthesis of 1.
Scheme 2
Our retrosynthetic analysis is outlined in Figure 2. The
dilactone framework of 1 was first disconnected into a “larger
stereogenic centers were introduced with excellent control
of the absolute configurations via two Evans/Crimmins
aldolizations.
The aldolization leading to 18 was best realized with (-)-
sparteine4d as the base (94% yield, dr >95:5). Use of TMEDA
under the otherwise identical conditions led to much lower
yields and diastereoselectivity. TMS protection8 and reductive
cleavage of the chiral auxiliary led to aldehyde 8 (not very
stable), which was directly treated with lithiated 7 to afford a
readily separable 2:3 mixture of 19a and 19b (Scheme 3).
With the stereochemistry on C-10 secured by redox trans-
formation of 19a to 19b, we set out to transform 19b9 into 21
through desilylation, diol protection, and deprotection/oxidation
at the C-3. The C-2/C-3 stereogenic centers were then generated
by reaction with 12. Removal of the TBS group in 22 was
achieved with HF·py. The C-C double/triple bonds were
saturated by hydrogenation in the presence of Et3N,10 which
Figure 2. Major fragments involved in this work.
fragment” 5 and a “smaller fragment” 6. The hydroxyacid 5
was then further disconnected into two major subunits, alkyne
7 and aldehyde 8. The synthesis of 7 is depicted in Scheme
1. Starting from 9, now a readily accessible5 chiral building
block, through TBS/MOM protections, removal of the
acetonide, oxidative cleavage of the vicinal diol and
Corey-Fuchs6 reaction, alkyne 7 was obtained in 75% over-
all yield (from 9).
(3) Wu, Y.-K.; Sun, Y.-P. Org. Lett. 2006, 8, 2831–2834.
(4) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127–2129. (b) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F.
J. Am. Chem. Soc. 1991, 113, 1047–1049. (c) Crimmins, M. T.; King, B. W.;
Tabet, E. A. J. Am. Chem. Soc. 1997, 119, 7883–7884. (d) Crimmins, M. T.;
Chaudhary, K. Org. Lett. 2000, 2, 775–777. (e) Crimmins, M. T.; King,
B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem. 2001, 66, 894–902.
(5) (a) Mulzer, J.; Pietschman, C.; Schollhorn, B.; Buschmann, J.; Luger,
P. Liebigs Ann. Chem. 1995, 1433-1439. For a practical access to multi-
ten grams of 9, see: (b) Wu, J.-Z.; Gao, J.; Ren, G.-B.; Zhen, Z.-B.; Zhang,
Y.-H.; Wu, Y.-K. Tetrahedron 2009, 65, 289–299.
(7) Marshall, J. A.; Schaaf, G.; Nolting, A. Org. Lett. 2005, 7, 5331–
5333.
(8) Without the TMS protection, the two C-10 epimers (19a and 19b
without the TMS group on C-8 OH) were inseparable on silica gel.
(9) (a) Essentially no reaction occurred if using Zn or Mg salt of 7. The
asymmetric protocol of Carreira (see, (b) Frantz, D. E.; Fassler, R.; Carreira,
E. M. J. Am. Chem. Soc. 2000, 122, 1806–1807) also failed to yield any
products here. (c) The relative configurations of 19a/b were established
through NOEs of their C-8 OH/C-10 OH acetonides.
(10) For a literature precedent using a primary amine for such a purpose,
see: Czech, B. P.; Barsch, R. A. J. Org. Chem. 1984, 49, 4076–4078.
(6) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769–3772.
Org. Lett., Vol. 11, No. 24, 2009
5639

Scheme 3
made it possible to remain an intact BnO- and consequently
The resulting 27 was transformed into the corresponding
Weinreb amide and ketone sequentially by reaction with AlMe3/
MeNH(OMe)·HCl and n-PrMgBr, respectively. The C-8′ ste-
reogenic center was then introduced by a Me4NBH(OAc)315
reduction. Removal of the TBS group and acetonization of the
diol provided alcohol 29, which on oxidation yielded the
aldehyde required for the next aldol reaction.
the C-6 OH required in the later THF-ring formation.
Mesyaltion leading to 24 was uneventful. Subsequent removal
of the acetonide group with TFA/MeOH-CH2Cl2 (1:1) did not
give the expected diol but a mono-THF species formed through
alkylation of the C-10 OH by the C-13 mesylate!11 Exposure
of this crude product to H2/Pd-C/THF followed by heating in
2,6-lutidine at 120 °C afforded the desired 25a in 93% yield.
Alternatively, 25a could also be obtained by treatment of 24
with H2/Pd-C (excess)/MeOH/rt for 2 h followed by heating
in 2,6-lutidine, though the yield was slightly lower (86%). In
the presence of CSA after prolonged reaction, the hydrogenation
alone could lead directly to diol 25b in 68% yield.12 Cleavage
of the chiral auxiliary in 25a with LiOH/H2O213 completed the
whole synthesis of 5.
The MgCl2/TMSCl16-mediated anti aldolization leading
to 27 was first attempted under the literature conditions
without success. However, when the amounts of MgCl2/Et3N
were increased from the literature recommended 0.1/2.0
equiv to 1.0/2.5 equiv, respectively, the desired 30 could be
isolated in 56% yield (from 29).17 Addition of NaSbF616 in
this case did not lead to any improvements but substantially
lower yield and diastereoselectivity.
Synthesis of 6 began with an Evans/Crimmins aldolization
The alcohol 30 was converted into 31 over three steps of
reactions: hydrogenation of the C-C double bond, mesyla-
tion of the C-3′ OH, and removal of the acetonide. Treatment
of 31 under the previously3 established 2,6-lutidine/120 °C
conditions led to 6 in 90% yield (dr 10:1 before separation).
Use of an even bulkier base, 2,6-di-tert-butylpyridine, to
replace 2,6-lutidine resulted in slightly better yield but worse
diastereoselectivity (dr 5:1). Better diastereoselectivity (dr
between aldehyde 2614 and acyloxazolidinone 12 (Scheme 4).
Scheme 4
(11) We are not aware of similar precedents in the literature; such an
etherification usually occurs only under basic conditions.
(12) We are not aware of any literature precedents.
(13) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987,
28, 6141–6144.
(14) Ramachandran, P. V.; Burghardt, T. E.; Reddy, M. V. R. J. Org.
Chem. 2005, 70, 2329–2331.
(15) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560–3578.
(16) (a) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am.
Chem. Soc. 2002, 124, 392–393. (b) Evans, D. A.; Downey, C. W.; Shaw,
J. T. Org. Lett. 2002, 4, 1127–1130.
(17) We are not aware of any precedents of application of this
protocol to complex enals with an eliminable ethereal group at the allylic
position.
5640
Org. Lett., Vol. 11, No. 24, 2009

95:5) could be obtained in neat pyridine at 110 °C, but the
yield of isolated 6 was only 62%.
P(O)N320 to afford azide 33. Further conversion of the azido
functionality into -NMe2 was troublesome. The literature2e
conditions (e.g., H2/Pd-C/HCHO/ HCO2H) led repeatedly
to complex mixtures. Ph3P or SnCl2 reduction followed by
treatment with NaBH3CN/HCHO/AcOH also resulted in
mixtures. Finally, we were pleased to find that treatment of
33 with n-Bu3SnH21 in refluxing toluene (in the absence of
any added radical initiators) could afford the desired
intermediate primary amine cleanly, which on further
exposure to NaBH3CN/ HCHO/AcOH led to end product22
1 in 92% yield.
The coupling between 5 and 6 (Scheme 5) under the
Yamaguchi18 conditions occurred smoothly despite the
Scheme 5
In conclusion, an effective enantioselective total synthesis
of pamamycin 621A was achieved. The characteristic THF’s
motifs were constructed from aldols in the presence of chiral
auxiliaries with configuration inversions at the positions ꢀ
to carbonyl groups. Elaboration of the C-1 and C-1′ was thus
greatly simplified. The basic nitrogen functionality was
introduced at a rather late stage, which greatly facilitated
isolation and characterization of the enantiopure intermedi-
ates. A number of interesting phenomena were observed,
including the unexpected THF-ring closures under acidic
conditions. Finally, an n-Bu3SnH reduction of azide to amine
was achieved for the first time in multifunctional/sensitive
substrates. Such a mild protocol may find broad applications
in total synthesis of other natural products.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (20672129, 20621062,
20772143) and the Chinese Academy of Sciences (“Knowledge
Innovation”, KJCX2.YW.H08) is gratefully acknowledged.
significantly increased steric crowding around the C-8′ OH
caused by the extra C-7′ methyl group (compared with its
counterpart in Kang’s2e synthesis19). Subsequent treatment
with LiOH/H2O2 yielded 32. The dilactone ring was then
closed in 66% yield using another Yamaguchi esterification.
Notably, at this step heating to 110 °C proved to be
necessary, as lower temperatures led to poor yields or even
complete failure.
Supporting Information Available: Selected experi-
ments, physical and spectroscopic data listing, 1H as well as
13C NMR spectra for 25a, 25b, 5, 6, “5 + 6”, 30′, 30′′, 31,
32, 32′, 32′′, 33, and 1. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL902290V
(20) Lal, B.; Pramanik, E. N.; Manhas, M. S.; Bose, A. K. Tetrahedron
Lett. 1977, 1977–1980.
The MOM group was hydrolyzed with 10% HBr. The
resulting alcohol was treated with Ph3P/DEAD/(PhO)2-
(21) Redlich, H.; Roy, W. Liebigs. Ann. Chem. 1981, 1215–1222.
(22) Stirring of the CDCl3 with K2CO3 before use made it easier to obtain
a “normal-looking” 1H NMR spectrum. Otherwise, the spectrum of 1 might
be different from run to run, with the N-methyl groups appearing at different
chemical shifts as the most prominent phenomenon. Another very interesting
phenomenon observed with 1 is that in CH2Cl2 its [R] is of opposite sign
to that in CHCl3!
(18) For Yamaguchi esterification, see: Yamaguchi, M.; Innaga, J.;
Hirata, K.; Saeki, H.; Katsuki, T. Bull. Chem. Soc. Jpn. 1979, 52, 1989–
1993.
(19) In other routes involving similar coupling, the C-8 OH was all
masked as either a TBS ether or an acetate (ref 2a,g,f).
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