A practical total synthesis of hapalosin, a 12-membered cyclic depsipeptide with multidrug resistance-reversing activity, by employing improved segment coupling and macrolactonization

Article abstract of DOI:10.1021/jo0497499

A practical total synthesis of hapalosin, a compound with multidrug resistance-reversing activity, has been carried out using an unprecedented macrolactonization strategy. One of the features of the new approach is the straightforward and fully stereocont

Full text of DOI:10.1021/jo0497499

A P r a ctica l Tota l Syn th esis of Ha p a losin , a 12-Mem ber ed Cyclic
Dep sip ep tid e w ith Mu ltid r u g Resista n ce-Rever sin g Activity, by
Em p loyin g Im p r oved Segm en t Cou p lin g a n d Ma cr ola cton iza tion †
Claudio Palomo,*,‡ Mikel Oiarbide,‡ J esu´s M. Garc´ıa,§ Alberto Gonza´lez,§ Raquel Pazos,‡
J ose´ M. Odriozola,§ Patricia Ban˜uelos,§ Mo´nica Tello,§ and Anthony Linden|
Departamento de Qu´ımica Orga´nica I, Facultad de Qu´ımica, Universidad del Pa´ıs Vasco,
Apdo. 1072, 20080 San Sebastia´n, Spain, and Departamento de Qu´ımica Aplicada,
Universidad Pu´blica de Navarra, Campus de Arrosad´ıa, 31006 Pamplona, Spain
qoppanic@sc.ehu.es
Received February 12, 2004
A practical total synthesis of hapalosin, a compound with multidrug resistance-reversing activity,
has been carried out using an unprecedented macrolactonization strategy. One of the features of
the new approach is the straightforward and fully stereocontrolled access to the key γ-amino
â-hydroxy carboxylic acid subunit via an efficient acetate aldol addition reaction with N-methyl
R-aminoaldehydes, which relies on a camphor-derived chiral lithium acetate enolate reagent. The
scope of this aldol reaction is investigated and its potential application to the synthesis of other
structurally related, biologically relevant compounds illustrated. Remarkably, the chiral tether in
the resulting γ-amino aldol adducts sterically protect the carbonyl group, thus avoiding intramo-
lecular cyclization during the amino group deprotection and the subsequent segment coupling event.
After successful segment coupling and smooth, clean release of the chiral auxiliary, a new
macrolactonization protocol, based on the principle of double activation of both reactive sites, is
applied, which leads to the 12-membered macrolactone hapalosin in unprecedented chemical
efficiency.
The phenomenon of drug resistance is recognized as
one of the most important obstacles in the effective
treatment and cure of cancer during chemotherapy.1 One
strategy to overcome this problem is the co-administra-
tion of agents that block specific mechanisms of drug
resistance. One form of drug resistance is known as
multidrug resistance (MDR), and several classes of
agents have been demonstrated to overcome the MDR
phenotype in experimental tumor systems.2 Despite
considerable progress, the biochemical origin of MDR is
not fully understood, while the molecular mechanism by
which these agents are capable of overcoming MDR may
be multiple.3 Among the active anti-MDR pharmaceuti-
cals, most share certain structural similarities from
which high lipophilicity and planarity, the latter posed
by the presence of two or more aromatic rings, seem to
be a prerequisite for circumventing MDR.2b Recently, the
isolation, characterization, and in vitro biological evalu-
ation of hapalosin 14 has indicated that other structural
concerns may also be implicated in reversing MDR.
Hapalosin is a structurally unique 12-membered cyclic
depsipeptide whose molecular architecture is completely
unrelated to that of the common MDR-reversing agents:
it is of very low symmetry and almost free of aromatic
rings. The structural backbone of 1 is comprised of the
union of two hydroxy acid subunits, and one γ-amino
â-hydroxy acid segment and contains five stereocenters
confined in a reduced space.
The total synthesis of hapalosin was first reported by
Armstrong5 in 1995 and relied on lactone formation as
the key macrocyclization step. Almost simultaneously,
Ghosh6 reported on an alternative macrocyclization
through lactam formation. Later publications7 describe
several other syntheses of 1, which also rely on this latter
strategy. These works have identified two major chal-
lenging elements: the synthesis and coupling of the C6-
C9 γ-amino â-hydroxy carboxylic acid subunit and the
realization of the 12-membered macrocyclization. The
inherent tendency of γ-amino esters to undergo intramo-
lecular cyclization to γ-lactams is a problem posed not
† Part of this work was presented at the meeting Perspectives of
the Chemistry of Natural Organic Products organized by Accademia
Nazionale dei Lincei in collaboration with Instituto Lombardo Acca-
demia di Scienze e Lettere (www.lincei.it), November 2002, Milan, on
the occasion of the 100th anniversary of the birth of Adolfo Quilico.
‡ Universidad del Pa´ıs Vasco.
§ Universidad Pu´blica de Navarra.
| X-ray analysis: Organisch-chemisches Institut der Universita¨t
Zu¨rich, Winterthurerstrasse 190, CH-8057, Zu¨rich, Switzerland.
(1) Atadja, P.; Watanabe, T.; Xu, H.; Cohen, D. Cancer Metast. Rev.
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10.1021/jo0497499 CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/08/2004
4126
J . Org. Chem. 2004, 69, 4126-4134

Total Synthesis of Hapalosin
SCHEME 1. P r ep a r a tion of Rea gen t 3
nitrogen atom is methylated in the product, one optional
route would begin from an otherwise protected amino
group which in a latter stage would be deprotected and
then methylated. A second option would begin directly
from the corresponding N-methyl R-amino aldehyde,
which would be readily available from the respective
N-methyl R-amino acid.12
F IGURE 1. First syntheses of hapalosin along with the
strategy proposed herein.
only during the synthesis and further coupling of the C6-
C9 subunit, but also during the macrolactamization step,
which typically proceeds in yields within the 20-40%
range.6,7 On the other hand, dimer formation usually
competes with lactonization involving 10 ( 2 membered
ω-hydroxy acids,8 a problem that probably accounts for
the low yield (13%) for the cyclization leading to hapal-
osin regardless of the reagent system employed.5 Herein,
we report a technologically advanced total synthesis of
hapalosin based on an acetate aldol approach as the key
reaction element to the γ-amino â-hydroxy carboxylic acid
subunit along with a new macrolactonization protocol
with improved chemical efficiency (Figure 1).
Prior reports from our laboratories have documented
the efficiency of the lithium enolate of methyl ketone 3,
Scheme 1, in successfully addressing the problem of the
insufficient stereoselectivity often encountered in the
“acetate” aldol addition and related reactions.13 On this
basis, it seemed reasonable to expect that this methyl
ketone reagent may be equally effective, in terms of
stereoselectivity, against N-methyl R-amino aldehyde
substrates. Furthermore, the chiral tether in reagent 3
seems to present a very crowded environment around the
carbonyl group, a structural feature that may be advan-
tageous for preventing the carbonyl function of the
resulting γ-amino aldol from an eventual intramolecular
cyclization event. If the above assumptions are correct,
the chiral tether in 3 would act not only as the chiral
controller of the process, but also as the carbonyl protect-
ing group during segment coupling and, as a result, a
straightforward access to highly functionalized γ-amino
aldol subunits should be made feasible in a very concise
fashion. Importantly, the synthesis of the required meth-
yl ketone 3 from (1R)-(+)-camphor 2 and acetylene, two
commodity chemicals available in bulk, is straightfor-
ward and high yielding, Scheme 1.
Resu lts a n d Discu ssion
Aceta te Ald ol Rea ction w ith N-Meth yl r-Am in o
Ald eh yd es. The synthesis we planned begins with the
construction of the C6-C9 segment followed by sequen-
tial assembly of the R-hydroxy acid unit (amide forma-
tion) and the C2-C4 propionate aldol subunit (ester
formation) and final macrocyclization through the yet-
unexplored lactone formation. The plan looked flexible
enough to be amenable to the synthesis of analogues, and
its major novelty relied on the unprecedented use of an
“acetate” aldol reaction with R-amino aldehydes as the
access to the γ-amino â-hydroxy carboxylic acid subunit.9
In general, acetate aldol addition reactions tend to be
poorly stereoselective,10 while reactions involving R-ami-
no aldehyde substrates usually require N,N-dibenzyl-
protected R-amino aldehydes for success.11 Since the
Concordant with our expectations, aldol product 5a ,
from the reaction of the lithium enolate of 3 with the
N-methyl R-amino aldehyde 4a , Scheme 2, was indeed
formed in 78% yield and, most significantly, as the sole
(10) For pertinent information on this subject, see: (a) Braun, M.
Angew. Chem., Int. Ed. Engl. 1987, 26, 24-37. (b) Braun, M. In
Advances in Carbanion Chemistry; Snieckus, V., Ed.; J AI Press:
London, 1992; Vol. 1, p 177. (c) Braun, M.; Sacha, H. J . Prakt. Chem.
1993, 335, 653-668.
(11) For more information, see: (a) J urzack, J .; Golewioski, A. Chem.
Rev. 1989, 89, 149-164. (b) Reetz, M. T. Chem. Rev. 1999, 99, 1121-
1162.
(12) (a) Coggins, J . R.; Benoiton, N. L. Can. J . Chem. 1971, 49,
8-1971. For leading references to more recent methods for the
preparation of N-methyl R-amino acids, see: (b) Cho, J . H.; Kim, B.
M. Tetrahedron Lett. 2002, 43, 1273-1276. (c) Di Gioia, M. L.; Leggio,
A.; Le Pera, A.; Ligouri, A.; Napoli, A.; Siciliano, C.; Sindona, G. J .
Org. Chem. 2003, 68, 7416-7421. (d) Aurelio, L.; Box, J . S.; Brownlee,
R. T. C.; Hughes, A. B.; Sleebs, M. M. J . Org. Chem. 2003, 68, 2652-
2667.
(13) For the preparation and applications of reagent 3, see: (a)
Palomo, C.; Gonza´lez, A.; Garc´ıa, J . M.; Landa, C.; Oiarbide, M.;
Rodr´ıguez, S.; Linden, A. Angew. Chem., Int. Ed. 1998, 37, 180-182.
(b) Palomo, C.; Oiarbide, M.; Aizpurua, J . M.; Gonza´lez, A.; Garc´ıa, J .
M.; Landa, C.; Odriozola, I.; Linden, A. J . Org. Chem. 1999, 64, 8193-
8200. (c) Palomo, C.; Oiarbide, M.; Gonza´lez-Rego, M. C.; Sharma, A.
K.; Garc´ıa, J . M.; Gonza´lez, A.; Landa, C.; Linden, A. Angew. Chem.,
Int. Ed. 2000, 39, 1063-1065. (d) Palomo, C.; Oiarbide, M.; Landa,
A.; Gonza´lez-Rego, M. C.; Garc´ıa, J . M.; Gonza´lez, A.; Odriozola, J .
M.; Mart´ın-Pastor, M.; Linden, A. J . Am. Chem. Soc. 2002, 124, 8637-
8643.
(7) (a) Wagner, B.; Beugelmans, R.; Zhu, J . Tetrahedron Lett. 1996,
36, 6557-6560. (b) Okuno, T.; Ohmori, V.; Nishiyama, S.; Yammamura,
S.; Nakamura, K.; Houk, K. N.; Okamoto, K. Tetrahedron 1996, 52,
14723-14734. (c) Dinh, T. Q.; Du, Y.; Smith, C. D.; Armstrong, R. W.
J . Org. Chem. 1997, 62, 6773-6783. (d) Haddad, M.; Botuha, C.;
Larcheveˆque, M. Synlett 1999, 1118-1120. (e) Hermann, C.; Pais, G.
C. G.; Geyer, A.; Ku¨hnert, S. M.; Maier, M. E. Tetrahedron 2000, 56,
8461-8471. (f) Hermann, C.; Giammasi, C.; Geyer, A.; Maier, M. E.
Tetrahedron 2001, 57, 8999-9010. (g) Kashihara, N.; To-e, S.; Naka-
mura, K.; Umezawa, K.; Yamamura, S.; Nishiyama, S. Bioorg. Med.
Chem. Lett. 2000, 10, 101-103. (h) O’Connell, C. E.; Salvato, K. A.;
Meng, Z.; Littlefield, B. A.; Schwartz, C. E. Bioorg. Chem. Lett. 1999,
9, 1541-1546.
(8) Bartra, M.; Urp´ı, F.; Vilarrasa, J . In Recent Progress in the
Synthesis of Antibiotics and Related Microbial Products; Lukacks, G.,
Ed.; Springer-Verlag: Berlin, 1993; Vol. 2, pp 1-66.
(9) For multistep processes targeting this segment, see: (a) Refer-
ences 5-7. (b) Pais, G. C. G.; Maier, M. E. J . Org. Chem. 1999, 64,
4551-4554. (c) Catasu´s, M.; Moyano, A.; Perica´s, M. A.; Riera, A.
Tetrahedron Lett. 1999, 40, 9309-9312. (d) Huang, P. Q.; Wang, S.
L.; Ye, J . L.; Ruan, Y. P.; Huang, Y. Q.; Zheng, H.; Gao, J . X.
Tetrahedron 1998, 54, 12547-12560. (f) Maier, M. E.; Hermann, C.
Tetrahedron 2000, 56, 557-561.
J . Org. Chem, Vol. 69, No. 12, 2004 4127

Palomo et al.
TABLE 1. Scop e for th e Dia ster eoselective Aceta te
Ald ol Ad d ition w ith r-Am in o Ald eh yd es
electronically effective, carbonyl group, and its lithium
enolate may be generated simply by using n-BuLi as the
base. Under these conditions, nucleophilic alkylation of
the carbonyl group was not detected at all. This effective
and unprecedented chiral tether-based carbonyl protec-
tion18 is of particular interest in that it provides a suitable
platform on which to build stereochemical motifs formally
derived from the acetate aldol reaction with more com-
plex N-methyl(alkyl) N-acyl R-amino aldehydes. For
example, exposure of the aldol 5a to hydrogen over
palladium on charcoal led to the formation of the N-
methyl derivative 6 without detection of any product
derived from intramolecular attack of the amino group
at the carbonyl function (Scheme 2).19 Subsequent coup-
ling of 6 with the acid chloride 7, the latter prepared from
the corresponding R-benzyloxy acid, provided hapalosin
segment 8 in 80% yield. Deprotection of the tertiary
hydroxyl group, further selective protection of the sec-
ondary carbinol as tert-butyldimethylsilyl(TBS) ether,
and final oxidative cleavage of the acyloin moiety in the
resulting 10 by using cerium ammonium nitrate (CAN),20
afforded the required C6-C12 fragment 11 in 60%
overall yield. It is also worth of noting that from this
latter operation, (1R)-(+)-camphor, the chiral auxiliary
of the approach is also released and can be easily
recovered and reused. Accordingly, all carbon atomsem-
ployed in the whole process are integrated in the final
product.
Scop e of th e Segm en t-Cou p lin g Ap p r oa ch . Given
the results noted above, it was considered to be instruc-
tive at this stage to get some insight into the potential
scope of this segment approach. For example, the syn-
thesis of a key structural portion of the powerful anti-
neoplastic agent dolastatin 1015 could be made feasible
in a few steps as shown in Scheme 3. Thus, N-methyl
γ-amino â-hydroxy carbonyl adduct 5b upon O-methyl-
ation21 and subsequent exposure of the resulting O-
methyl ether 12 to hydrogen over palladium on charcoal
gave N-methylamine 13 as a stable intermediate whose
structure was unambiguously determined by an X-ray
crystal structure analysis. An amide coupling with Cbz-
a
For (Xc-OSiMe3), see Scheme 2. b Yield of isolated product after
silica gel chromatography. c Using 2 equiv of aldehyde. Yield over
the two steps: aldol reaction and desilylation of adducts with
TBAF. For further details, see the Supporting Information.
d
diastereomeric product. This result appears to be quite
regular for the other N-methyl R-amino aldehydes tested,
Table 1, including N-BOC R-aminoaldehydes 4f,g,14 and,
from the adducts obtained, diverse γ-amino â-hydroxy
carboxylic acids may be formed, vide infra. Both N-
methyl and N-unsubstituted γ-amino â-hydroxy carboxy-
lic acids are found in other relevant compounds such as
dolastatin,15 didemnins,16 and pepstatin.17
(18) For achiral appendages used to sterically protect ketone and
carboxylic acid carbonyls, see the following. 1,1,1-Triphenylmethyl
group: (a) Seebach, D.; Ertas, M.; Locher, R.; Schweizer, W. B. Helv.
Chim. Acta 1985, 68, 264-282. (b) Ertas, M.; Seebach, D. Helv. Chim.
Acta 1985, 68, 961-968. 2,2,6,6-Tetramethylpyperidines: (c) Seebach,
D.; Locher, R. Angew. Chem., Int. Ed. Engl. 1979, 18, 957-958. 2,6-
Di-tert-butyl-4-methoxyphenyl: (d) Heathcock, C. H.; Pirrung, M. C.;
Montgomery, S. H.; Lampe, J . Tetrahedron 1981, 37, 4087-4095. Tris-
(2,6-diphenylbenzyl)silyl group: (e) Iwasaki, A.; Kondo, Y.; Maruoka,
K. J . Am. Chem. Soc. 2000, 122, 10238-10239
Concurrent with the observations noted above, it was
found that methyl ketone 3 has a sterically hindered, but
(19) When N-deprotection was carried out on substrate I, pyrrolidine
II was produced as major product. An X-ray crystal-structure analysis
of II confirmed both structure and stereochemical assignment. We
thank M. C. Gonza´lez-Rego for the synthesis of compounds I and II.
(14) For acetate aldol reactions with N-Boc R-aminoaldehydes, see:
(a) Swing, W. R.; J oullie, M. M. Heterocycles 1988, 27, 2843-2850. (b)
Devant, R. M.; Radunz, H.-E. Tetrahedron Lett. 1988, 29, 2307-2310.
(c) Wuts, P. G. M.; Putt, S. R. Synthesis 1989, 951-953.
(15) (a) Pettit, G. R.; Kamano, Y.; Herald, C. L.; Tuinman, A. A.;
Boetner, F. E.; Kizu, H.; Schmidt, J . M.; Baczynskyj, L.; Tomer, K. B.;
Bontems, R. J . J . Am. Chem. Soc. 1987, 109, 6883-6885. (b) Shioiri,
T.; Yamada, Y. Synlett 2000, 184-201.
(16) (a) Rinehart, K. L., J r.; Gloer, J . B.; Cook, J . C., J r.; Mizsak, S.
A.; Scahill, T. A. J . Am. Chem. Soc. 1981, 103, 1857-1859. (b) Liang,
B.; Richard, D. J .; Portonovo, P. S.; J oullie, M. M. J . Am. Chem. Soc.
2001, 123, 4469-4474. (c) Vera, M. D.; J oullie, M. M. Med. Res. Rev.
2002, 22, 102-145.
(17) (a) Umezawa, H.; Aoyagi, T.; Morishima, H.; Matsuzaki, H. J .
Antibiot. 1970, 23, 259-262.
(20) Review: Ho, T.-L. Synthesis 1973, 347-354.
(21) (a) Diem, M. J .; Burow, D. F.; Fry, J . L. J . Org. Chem. 1977,
42, 1801-1802. (b) Pettit, G. R.; Grealish, M. P. J . Org. Chem. 2001,
66, 8640-8642.
4128 J . Org. Chem., Vol. 69, No. 12, 2004

Total Synthesis of Hapalosin
SCHEME 2. Syn th esis of Segm en t C6-C12
SCHEME 3. P ep tid e Cou p lin gs en Rou te to Dola sta tin 10
L-valine 14, using BroP under the conditions developed
by Shioiri and Hamada22 for similar couplings, provided
15 in 81% yield. This adduct upon N-deprotection and
further coupling with another Cbz-L-valine unit afforded
coupling product 16 in 60% yield, which upon desilylation
and oxidative treatment with CAN gave R,R,γ-tripeptide
17 in 63% yield over the two steps along with the recovery
of camphor.
CAN is tolerant with the methyl ether, the Cbz protecting
group, and the amide function.23
Com p letion of th e Syn th esis of Ha p a losin . Apart
from the problems associated with the synthesis and
coupling of the γ-amino â-hydroxy carboxylic acid seg-
ment noted above, in the reported syntheses of hapalosin
the realization of the 12-membered macrocyclization also
proved to be problematic. In an effort to improve earlier
results, we decided to investigate the alternative yet
unprecedented macrolactonization route depicted in
Scheme 4. To this end, carboxylic acid 11, upon conver-
sion into its acid chloride and subsequent coupling with
the â-hydroxy benzyl ester 18,7b afforded the coupling
One interesting consequence of these results is that
by making use of iterative couplings more complex
γ-amino aldol-derived products would be accessible with
minimum functional group protection/deprotection ma-
nipulations. On the other hand, from all of the above
cases, it is worth noting that the scission promoted by
(23) Catalytic hydrolysis of R-peptides by the action of CAN at
reaction temperatures of about 50 °C has been reported recently:
Takarada, T.; Yashiro, M.; Komiyama, M. Chem. Eur. J . 2000, 6,
3906-3913.
(22) Shioiri, T.; Hayashi, K.; Hamada, Y. Tetrahedron 1993, 49,
1913-1924.
J . Org. Chem, Vol. 69, No. 12, 2004 4129

Palomo et al.
SCHEME 4. Ad va n ced Segm en t Cou p lin g a n d F in a l Ma cr ola cton iza tion
product 19 in 80% yield. Further deprotection of the
benzyl ester and ether groups in 19 provided 20 in 98%
yield, which is ready for cyclization.
The hydroxy acid 20, however, was found to be
resistant to cyclization with the use of common reagent
systems such as 2,4,6-trichlorobenzoyl chloride-N,N-
diisopropylethylamine (DIPEA) and DMAP,24 2-chloro-
N-methylpyridinium iodide-DMAP,25 and bis(2-oxo-3-
F IGURE 2. Double-activation principle27 upon combination
of di-2-pyridyl ketone oxime esters and Cu(OTf)2.
oxazolidinyl)phosphinic chloride (BOP-Cl)-DIPEA and
DMAP.26 In these instances, the expected cyclized product
could be formed only in less than 10%-15% yields.
At this stage, we focused on methods based upon the
concept of “double activation”27 with the aid of external
metal cations which in certain situations has proven to
be effective for difficult macrolactonization events.28 In
particular, generation of the (E)-phenyl 2-pyridyl O-acyl
oximes has been shown to be very efficient for carboxyl
group activation toward O-alkyl and O-benzyl ester
formation.29 Our own group has recently documented that
the related di-2-pyridyl ketone oxime esters react ef-
ficiently with R-amino acid salts to give the corresponding
peptide coupling products.30 Encouraged by these prece-
dents, and on the basis of models depicted in Figure 2,
the di-2-pyridyl ketone oxime ester of ω-hydroxy acid 20
was prepared by treatment with di-2-pyridyl ketone
oxime and N-(3-dimethylaminopropyl)-N′-ethylcarbodi-
imide hydrochloride (EDC) in dichloromethane in the
presence of a catalytic amount of DMAP. The resulting
ketone oxime ester was kinetically stable, and no spon-
taneous cyclization was observed in any appreciable
extent. Fortunately, when 1 equiv of a metal salt, such
as Cu(OTf)2, was added to an acetonitrile solution of the
oxime ester, a smooth reaction took place under refluxing
conditions resulting in the formation of the expected
cyclizized product, which was desilylated by treatment
with a HF-pyridine solution to afford hapalosin 1 in 54%
overall yield from 20. This is the highest yield obtained
1
to date in this crucial macrocyclization process.31 The H
NMR analysis of synthetic 1 showed the presence of cis/
trans conformers around the amide function in a 2:1
ratio.
Con clu sion s
A concise synthesis of γ-amino â-hydroxy carboxylic
acid segments, which are the key structural constituents
of biologically important compounds through a diaster-
eoselective aldol methodology, is reported. The method
is based on a chiral acetate reagent which shows several
beneficial features: (i) aldol reactions with R-amino
aldehydes occur under virtually perfect diastereocontrol;
(ii) γ-amino aldol adducts show a sterically protected
carbonyl group, so that no side products from intramo-
lecular cyclization are observed; (iii) such steric protection
of the carbonyl allows for subsequent coupling events to
proceed in high efficiency, and again without concomitant
formation of undesired side products; and (iv) the aux-
iliary cleavage by treatment with CAN takes place
smoothly, being tolerant of the fragment functionality.
(24) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989-1993.
(25) (a) Mukaiyama, T.; Usui, M.; Saigo, K. Chem. Lett. 1976, 49-
52. (b) Evans, D. A.; Kaldor, S. W.; J ones, T. K.; Clardy, J .; Stout, T.
J . J . Am. Chem. Soc. 1990, 112, 7001-7031.
(26) Corey, E. J .; Hua, D. H.; Pan, B.-C.; Seitz, S. P. J . Am. Chem.
Soc. 1982, 194, 6818-6820.
(27) Corey, E. J .; Nicolaou, K. C. J . Am. Chem. Soc. 1974, 96, 5614-
5616.
(28) For reviews, see: (a) Back, T. G. Tetrahedron 1977, 33, 3041-
3059. (b) Masamune, S.; Bates, G. S.; Corcoran, J . W. Angew. Chem.,
Int. Ed. Engl. 1977, 16, 585-607. (c) Reference 8.
(29) Miyasaka, T.; Ishizu, H.; Sawada, A.; Fujimoto, A.; Noguchi,
S. Chem. Lett. 1986, 871-874.
(30) Palomo, C.; Palomo, A. L.; Palomo, F.; Mielgo, A. Org. Lett.
2002, 4, 4005-4008.
(31) The corresponding (E)-phenyl-2-pyridyl O-acyl oxime of acid 20
also furnished the desired cyclisized product in 40-45% yields.
4130 J . Org. Chem., Vol. 69, No. 12, 2004

Total Synthesis of Hapalosin
128.3, 127.8, 127.7, 127.6, 127.5, 90.6, 90.5, 68.6, 67.4, 67.1,
63.1, 51.9, 50.9, 45.2, 43.0, 40.3, 34.1, 31.7, 31.6, 30.2, 30.1,
29.1, 25.9, 25.8, 25.4, 22.7, 20.9, 20.3, 16.4, 15.7, 14.2, 11.4,
11.3, 10.9, 1.7.
Finally, it is demonstrated that the key macrocyclization
to hapalosin can be carried out through a previously
unrealized macrolactonization strategy, by the develop-
ment of a novel macrolactonization reagent system.
(1R)-2-en d o-[(3R)-3-((2′S)-N-Ben zyloxyca r bon ylp yr r o-
lid in yl)-3-h yd r oxyp r op a n oyl]-2-exo-t r im et h ylsilyloxy-
1,7,7-tr im eth ylbicyclo[2.2.1]h ep ta n e (5e). The procedure
described above was employed at a 15 mmol aldehyde scale,
with stirring at -78 °C for only 1 h instead of 3 h, to afford
product 5e as an oil (4.89 g, 65%): [R]25D ) -40 (c ) 1.0, CH2-
Cl2); IR (neat) ν ) 2956, 1700, 1413, 841; 1H NMR (200 MHz,
DMSO-d6, 90 °C) δ ) 7.37-7.28 (m, 5H), 5.11 (d, J ) 13 Hz,
1H), 5.04 (d, J ) 13 Hz, 1H), 4.57 (sb, 1H), 4.35 (m, 1H), 3.79
(m, 1H), 3.46 (m, 1H), 3.25 (m, 1H), 2.97 (dd, J ) 8.4, 17.9 Hz,
1H), 2.47 (m, 1H), 2.29 (dd, J ) 3.3, 17.9 Hz, 1H), 2.06-1.48
(m complex, 7 H), 1.26 (m, 1H), 1.04 (s, 3H), 0.97 (m, 1H), 0.94
(s, 3H), 0.80 (s, 3H), 0.68 (m, 1H), 0.09 (s, 9H); 13C NMR (50
MHz, DMSO-d6, 90 °C) δ ) 207.6, 154.1, 136.8, 127.8, 127.1,
126.9, 89.9, 65.9, 65.5, 61.7, 51.0, 50.1, 46.6, 44.6, 42.6, 39.6,
29.2, 25.2, 25.0, 23.3, 20.4, 19.8, 10.5, 1.3.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e P r ep a r a tion of N-Meth yl
r-Am in o Ald eh yd es (4). DIBAL (1 M solution in hexane, 0.04
mol, 34 mL) was added dropwise to a stirred solution of the
corresponding N-methylamino acid methyl ester12a (0.02 mol)
in dry toluene (60 mL) at -78 °C and under an N2 atmosphere.
The rate of addition was adjusted so as to keep the internal
temperature below -65 °C. Once the addition was complete,
the reaction mixture was stirred for an additional 2 h at -78
°C and then quenched by slowly adding 7.8 mL of cold (-78
°C) MeOH (H2 evolution). The rate of addition was again
adjusted so as to keep the internal temperature below -65
°C. The resulting white emulsion was slowly poured into 1 N
HCl (130 mL) at 0-5 °C, and the aqueous mixture was then
extracted with EtOAc (3 × 130 mL). The combined organic
layers were washed with brine (130 mL), dried with MgSO4,
filtered, and concentrated under vacuum. The residue was
purified by flash column chromatography on silica gel (mix-
tures of ethyl acetate/hexanes as eluent). Aldehyde 4h was
prepared in a different manner. See the Supporting Informa-
tion.
Gen er a l P r oced u r e for th e Ald ol Rea ction of th e
Lith iu m En ola te of 3 a n d r-Am in o Ald eh yd es. n-Butyl-
lithium (2.5M in hexane, 2.7 mL, 6.7 mmol) was added to a
solution of the methyl ketone 3 (1.8 g, 6.7 mmol) in THF (20
mL) at -78 °C. The reaction mixture was stirred for 1 h, and
then a solution of the aldehyde 4 (4.5 mmol) in THF (9 mL)
was added dropwise. After 3 h of stirring, the reaction was
quenched with aqueous NH4Cl (10 mL), the cold bath removed,
and the mixture stirred until it reached room temperature.
The reaction mixture was then extracted with CH2Cl2, and the
organic layer was washed with NH4Cl, dried over MgSO4, and
evaporated under vacuum. Purification was effected by flash
column chromatography, using a 1:30 mixture of EtOAc-
hexane as the eluent.
(1R)-2-en d o-[(3R,4S)-3-Hyd r oxy-4-(N-m eth yla m in o)-5-
p h en ylp en ta n oyl]-2-exo-tr im eth ylsilyloxy-1,7,7-tr im eth -
ylbicyclo[2.2.1]h ep ta n e (6). A round-bottom flask containing
a mixture of 5a (5.65 g, 10 mmol) and Pd/C (10% Pd, 1.06 g,
1 mmol) in EtOAc (100 mL) was stirred for 3 h at 25 °C under
a balloon full of H2. Then the flask was purged with N2, and
the mixture was filtered through a short column of Celite and
washed well with EtOAc. The solvent was removed under
reduced pressure to afford product 6 (4.23 g, 98%): [R]25
)
D
+20 (c ) 1.0, CH2Cl2); IR (neat) ν ) 3467, 2956, 1707, 1454,
1122, 841; 1H NMR (200 MHz, CDCl3) δ ) 7.32-7.16 (m, 5H),
4.16 (m, 1H), 3.06 (dd, J ) 9.2, 17.9 Hz, 1H), 2.82-2.36 (m,
4H), 2.38 (s, 3H), 1.83-0.64 (m, 7H), 1.03 (s, 3H), 1.01 (s, 3H),
0.80 (s, 3H), 0.11 (s, 9H); 13C NMR (50 MHz, CDCl3) δ ) 211.5,
138.7, 129.0, 128.4, 126.2, 90.6, 66.2, 64.5, 51.7, 50.8, 45.1, 41.1,
40.1, 35.0, 34.5, 30.0, 25.7, 20.9, 20.3, 11.3, 1.7; MS (ESI, m/z)
calcd for C25H42NO3Si (M + H+) 432.30, found 432.5.
(2S)-Ben zyloxy-3-m eth ylbu ta n oyl Ch lor id e (7). A solu-
tion of LiOH‚H2O (1.68 g, 40 mmol) in water (6.8 mL) was
added dropwise to a solution of methyl (2S)-benzyloxy-3-
methylbutanoate32 (2.22 g, 10 mmol) in methanol (20 mL) at
room temperature. The mixture was stirred at reflux for 3 h,
and then water (15 mL) was added. The reaction mixture was
extracted with CH2Cl2 (2 × 50 mL), and the aqueous layer was
acidified with concentrated HCl and extracted with CH2Cl2 (3
× 50 mL). The combined organic extracts were dried over
MgSO4 and filtered, and the solvent was removed under
reduced pressure to give (2S)-benzyloxy-3-methylbutanoic
acid: yield 1.89 g, 91%; [R]25D ) -84.0 (c ) 1.0, THF); IR (neat)
ν ) 3180, 2965, 1712, 1454, 1208, 1071, 697; 1H NMR (200
MHz, CDCl3) δ ) 7.34-7.29 (m, 5H), 4.71 (d, J ) 11.9 Hz,
1H), 4.46 (d, J ) 11.6 Hz, 1H), 3.79 (d, J ) 4.6 Hz, 1H), 2.15
(1R)-2-en d o-[(3R,4S)-4-(N-Ben zyloxyca r bon yl-N-m eth -
yla m in o)-3-h yd r oxy-5-p h en ylp en t a n oyl]-2-exo-t r im et h -
ylsilyloxy-1,7,7-tr im eth ylbicyclo[2.2.1]h ep ta n e (5a ). The
procedure described above was employed at
a 15 mmol
aldehyde scale, with stirring at -78 °C for only 2 h instead of
3 h, to afford product 5a as a colorless oil (6.6 g, 78%): [R]25
D
) -25 (c ) 1.0, CH2Cl2); IR (neat) ν ) 3478, 2956, 1700, 1497,
1454, 841; 1H NMR (200 MHz, DMSO-d6, 90 °C) δ ) 7.31-
7.17 (m, 10H), 4.92 (sb, 2H), 4.17 (m, 2H), 3.18 (dd, J ) 2.9,
14.7 Hz, 1H), 3.00 (dd, J ) 8.1, 18.3 Hz, 1H), 2.80 (m, 1H),
2.67 (s, 3H), 2.50-2.32 (m, 2H), 1.71 (m, 1H), 1.55 (m, 1H),
1.25 (m, 1H), 1.07-0.61 (m, 3H), 1.04 (s, 3H), 0.88 (s, 3H), 0.80
(s, 3H), 0.10 (s, 9H); 13C NMR (50 MHz, CDCl3) δ of major
rotamer ) 213.5, 156.4, 138.6, 136.7, 128.2, 127.7, 127.6, 127.4,
126.0, 90.6, 69.4, 66.7, 63.2, 51.8, 50.9, 45.1, 42.9, 40.3, 33.9,
33.0, 30.1, 25.7, 20.8, 20.2, 11.1, 1.7; MS (ESI, m/z) calcd for
(m, 1H), 1.01 (d, J ) 2.9 Hz, 3H), 0.98 (d, J ) 2.9 Hz, 3H); 13
C
NMR (50 MHz, CDCl3) δ ) 177.8, 137.1, 128.3, 127.9, 127.8,
82.6, 72.8, 31.5, 18.9, 17.4. To a solution of this acid (1.25 g, 6
mmol) in CH2Cl2 (24 mL) cooled to 0 °C was added dropwise
oxalyl chloride (1.55 mL, 18 mmol). The mixture was stirred
at room temperature for 3 h, the solvent and excess oxalyl
chloride were removed under reduced pressure, and the crude
product was used in the next reaction as is.
C
33H48NO5Si (M + H+) 566.33, found 566.2.
(1R)-2-en d o-[(3R,4S,5S)-4-(N-Ben zyloxyca r bon yl-N-m e-
t h yla m in o)-3-h yd r oxy-5-m et h ylh ep t a n oyl]-2-exo-t r im e-
th ylsilyloxy-1,7,7-tr im eth ylbicyclo[2.2.1]h eptan e (5b). The
procedure described above was employed using an aldehyde/3
molar ratio of 2:1 (15:7.5 mmol), with stirring at -78 °C for
only 30 min instead of 3 h, to afford product 5b as a colorless
(1R)-2-en d o-[(3R,4S)-4-(N-((S)-2-Ben zyloxy-3-m eth ylb-
u tan oyl)-N-m eth ylam in o)-3-h ydr oxy-5-ph en ylpen tan oyl]-
2-exo-tr im eth ylsilyloxy-1,7,7-tr im eth ylbicyclo[2.2.1]h ep -
ta n e (8). To a solution of 6 (2.16 g, 5 mmol) and DMAP (1.47
g, 12 mmol) in CH2Cl2 (25 mL) cooled to 0 °C was added a
solution of (2S)-benzyloxy-3-methylbutanoyl chloride 7 (1.36
g, 6 mmol) in CH2Cl2 (5 mL). The mixture was stirred at room
temperature for 3 h and then washed with 1 N HCl (3 × 20
mL) and with a saturated solution of NaHCO3 (2 × 20 mL).
oil (5.98 g, 75%): [R]25 ) +8.1 (c ) 1.0, CH2Cl2); IR (neat) ν
D
) 3488, 2957, 1697, 1253, 1150, 1088, 840; 1H NMR (200 MHz,
DMSO-d6, 90 °C) δ ) 7.34 (m, 5H), 5.09 (m, 2H), 4.37 (m, 1H),
3.73 (m, 1H), 2.97 (m, 1H), 2.93 (s, 3H), 2.75 (s, 1H), 2.45 (m,
1H), 2.32 (m, 1H), 1.72 (m, 2H), 1.55 (m, 2H), 1.27 (m, 2H),
1.10-0.38 (m, 3H), 1.04 (s, 3H), 0.97 (d, J ) 6.6 Hz, 3H), 0.90
(s, 3H), 0.87 (t, J ) 7.0 Hz, 3H) 0.81 (s, 3H), 0.09 (s, 9H); 13C
NMR (50 MHz, CDCl3) δ both rotamers ) 212.9, 157.4, 136.8,
(32) Sly, W.-R.; Swing, W. R.; Harris, B. D.; J oullie´, M. M. J . Am.
Chem. Soc. 1990, 112, 7659-7672.
J . Org. Chem, Vol. 69, No. 12, 2004 4131

Palomo et al.
The organic layer was dried over MgSO4, and the solvent was
removed under reduced pressure. The residue was purified by
column chromatography (EtOAc-hexane 1:40) to afford prod-
(3R,4S)-4-(N-((S)-2-Ben zyloxy-3-m et h ylb u t a n oyl)-N-
m eth yla m in o)-3-ter t-bu tyld im eth ylsilyloxy-5-p h en ylp en -
ta n oic Acid (11). A solution of cerium ammonium nitrate
(CAN) (3.28 g, 6 mmol) in water (12 mL) was added dropwise
to a solution of 10 (1.33 g, 2 mmol) in acetonitrile (24 mL) at
0 °C, and the mixture was stirred at the same temperature
for 30 min. Then water (6 mL) was added and the mixture
was extracted with CH2
uct 8 as a solid (2.49 g, 80%): mp 115-116 °C; [R]25 ) -57.0
D
(c ) 1.0, CH2Cl2); IR (neat) ν ) 3443, 2958, 1702, 1635, 1497,
1454, 1150, 842; 1H NMR (200 MHz, DMSO-d6, 90 °C) δ )
7.30-7.09 (m, 10H), 4.87 (m, 1H), 4.80 (m, 1H), 4.25 (m, 1H),
3.91 (d, J ) 11.0 Hz, 1H), 3.78 (d, J ) 6.2 Hz, 1H), 3.72 (d, J
) 12.8 Hz, 1H), 3.10 (dd, J ) 8.8, 17.6 Hz, 1H), 3.10 (m, 1H),
2.88 (m, 1H), 2.88 (s, 3H), 2.48 (d, J ) 4.4 Hz, 1H), 2.21 (d, J
) 17.6 Hz, 1H), 1.76 (m, 3H), 1.56 (m, 1H), 1.26 (m, 1H), 1.08-
0.71 (m, 2H), 1.05 (s, 3H), 0.92 (s, 3H), 0.86 (d, J ) 6.6 Hz,
3H), 0.80 (s, 3H), 0.78 (d, J ) 6.6 Hz, 3H), 0.13 (s, 9H); 13C
NMR (50 MHz, CDCl3) δ ) 213.0, 172.3, 138.3, 137.8, 129.3,
129.0, 128.6, 128.4, 128.1, 127.7, 127.5,127.4, 126.4, 90.7, 83.0
(broad), 70.7, 70.0, 51.9, 51.0, 45.2, 43.2, 40.4, 32.0, 30.6, 30.3,
25.8, 20.9, 20.3, 19.3, 18.4, 11.5, 1.8; MS (ESI, m/z) calcd for
Cl2 (2 × 50 mL). The combined organic
extracts were dried over MgSO4 and filtered, and the solvent
was removed under reduced pressure. The crude product was
purified by column chromatography (eluant: ethyl acetate/
hexane 1:10) to afford (1R)-(+)-camphor in the first fractions
and compound 11 in the subsequent fractions (0.91 g, 86%):
mp 118 °C; [R]25 ) -60.5 (c ) 1.0, CH2Cl2); IR (neat) ν )
D
1
2957, 2930, 1729, 1620, 1497, 1470, 836; H NMR (200 MHz,
CDCl3) δ ) 11.00 (sb, 1H), 7.30-7.05 (m, 10H), 4.40 (m, 1H),
4.20 (d, J ) 12.1 Hz, 1H), 3.63 (d, J ) 6.6 Hz, 1H), 3.63 (m,
1H), 3.27 (d, J ) 6.6 Hz, 1H), 2.84 (s, 3H), 2.84-2.38 (m, 4H),
1.84 (m, 1H), 0.96 (s, 9H), 0.93 (d, J ) 6.6 Hz, 3H), 0.70 (d, J
) 6.6 Hz, 3H), 0.18 (s, 3H); 13C NMR (50 MHz, CDCl3) δ of
major rotamer ) 174.7, 172.8, 138.0, 137.6, 128.8, 128.6, 128.3,
128.1, 127.9, 127.7, 127.6, 127.3, 126.4, 82.1, 70.7, 70.2, 40.9,
33.9, 30.2, 25.8, 19.1, 17.9, -4.1, -4.7; MS (ESI, m/z) calcd
for C30H44NO5Si (M - H+) 526.30, found 526.4. Anal. Calcd
for C30H45NO5Si (527.85): C, 68.26; H, 8.61; N, 2.65. Found:
C, 68.32; H, 8.59; N, 2.67.
(1R)-2-en d o-[(3R,4S,5S)-4-(N-Ben zyloxyca r bon yl-N-m e-
th yla m in o)-3-m eth oxy-5-m eth ylh ep ta n oyl]-2-exo-tr im e-
th ylsilyloxy-1,7,7-tr im eth ylbicyclo[2.2.1]h eptan e (12). Pro-
ton Sponge (1.393 g, 6.5 mmol) and trimethyloxonium
tetrafluoroborate (0.924 g, 6.25 mmol) were added to a solution
of 5b (1.33 g, 2.5 mmol) in CH2Cl2 (30 mL) over 4 Å molecular
sieves 4 Å (1.1 g) at 0 °C. The mixture was stirred at room
temperature for 24 h and then was filtered through a short
column of Celite, and the solvent was removed under reduced
pressure. The crude product was purified by column chroma-
tography (eluant: ethyl acetate/hexane 1:35): yield 1.02 g,
75%; [R]25D ) +7.0 (c ) 1.0, CH2Cl2); IR (neat) ν ) 2958, 1701,
1251, 1151, 1089, 841; 1H NMR (200 MHz, CDCl3) (data of
both rotamers unless otherwise noted) δ ) 7.31 (sb, 5H), 5.16
(d, J ) 13.2 Hz, 1H), 5.07 (d, J ) 13.2 Hz, 1H), 4.03 (m, 2H),
3.33 (s, 3H, single rotamer), 3.22 (s, 3H, single rotamer), 3.20
(m, 1H), 2.78 (s, 3H), 2.54 (dd, J ) 5.1, 11.7 Hz, 1H), 2.17 (db,
J ) 18.3 Hz, 1H), 1.80-0.45 (m, 9H, complex), 1.02 (s, 3H),
0.88 (m, 9H), 0.79 (s, 3H), 0.07 (s, 9H); 13C NMR (50 MHz,
CDCl3) δ (both rotamers) ) 208.5, 208.4, 157.1, 157.0, 137.1,
136.8, 128.2, 127.9, 127.7, 127.5, 127.3, 90.4, 76.1, 76.0, 67.2,
66.7, 60.1, 57.9, 57.8, 51.4, 50.8, 45.2, 40.8, 40.2, 33.7, 33.4,
31.5, 30.9, 29.9, 26.0, 25.9, 25.8, 20.9, 20.3, 16.1, 16.0, 11.3,
10.8, 2.2, 1.6, 1.0.
C
C
37H56NO5Si (M + H+) 622.39, found 622.4. Anal. Calcd for
37H55NO5Si (621.93): C, 71.44; H, 8.93; N, 2.25. Found: C,
71.48; H, 8.91; N, 2.27.
(1R)-2-en d o-[(3R,4S)-4-(N-((2S)-Ben zyloxy-3-m eth ylbu -
ta n oyl)-N-m eth yla m in o)-3-h yd r oxy-5-p h en ylp en ta n oyl]-
1,7,7-tr im eth ylbicyclo[2.2.1]h ep ta n -2-ol (9). To a solution
of 8 (1.86 g, 3 mmol) in THF (60 mL) was added TBAF (1 M
in THF, 4.5 mL, 4.5 mmol) at room temperature, and the
mixture was stirred for 30 min at the same temperature. Then,
the solvent was removed under reduced pressure and the crude
was filtered through a short column of silica gel using CH2Cl2
as eluant. The solvent was removed under reduced pressure
to afford compound 9 as a solid (1.57 g, 95%): mp 130-131
°C; [R]25 ) -77.0 (c ) 1.0, CH2Cl2); IR (neat) ν ) 3381, 2957,
D
1
1702, 1631, 1496, 1454, 1082; H NMR (200 MHz, DMSO-d6,
90 °C) δ ) 7.30-7.09 (m, 10H), 4.93 (s, 1H), 4.83 (m, 1H), 4.83
(d, J ) 5.5 Hz, 1H), 4.15 (m, 1H), 3.97 (d, J ) 11.7 Hz, 1H),
3.77 (d, J ) 11.0 Hz, 1H), 3.75 (d, J ) 4.0 Hz, 1H), 3.21 (m,
1H), 3.17 (dd, J ) 8.8, 16.1 Hz, 1H), 2.88 (m, 1H), 2.88 (s, 3H),
2.26 (m, 2H), 1.85 (m, 1H), 1.78-1.51 (m, 3H), 1.26 (m, 1H),
1.12-0.73 (m, 2H), 1.12 (s, 3H), 0.94 (s, 3H), 0.87 (d, J ) 6.6
Hz, 3H), 0.80 (s, 3H), 0.75 (d, J ) 7.0 Hz, 3H); 13C NMR (50
MHz, CDCl3) δ of major rotamer ) 214.1, 173.6, 138.0, 137.5,
130.8, 129.2, 128.8, 128.4, 128.1, 127.7, 127.5, 127.2, 126.8,
126.5, 87.8, 84.2, 71.1, 51.7, 51.0, 45.1, 41.4, 32.8, 30.6, 30.3,
26.2, 20.9, 20.6, 18.9, 18.7, 11.3, 1.0; MS (ESI, m/z) calcd for
C
C
34H48NO5 (M + H+), 550.36, found 550.4. Anal. Calcd for
34H47NO5 (549.75): C, 74.27; H, 8.63; N, 2.55. Found: C,
74.32; H, 8.61; N, 2.57.
(1R)-2-en d o-[(3R,4S)-4-(N-((S)-2-Ben zyloxy-3-m eth ylb-
u ta n oyl)-N-m eth yla m in o)-3-ter t-bu tyld im eth ylsilyloxy-
5-p h en ylp en ta n oyl]-1,7,7-tr im eth ylbicyclo[2.2.1]h ep -ta n -
2-ol (10). Pyridine (1.44 mL, 17.8 mmol) and tert-but-
yldimethylsilyl trifluoromethanesulfonate (2.75 mL, 12 mmol)
were added to a solution of 9 (1.65 g, 3 mmol) in CH2Cl2 (15
mL) at room temperature. The mixture was stirred at this
temperature for 15 h and then was washed with a saturated
solution of NaHCO3 (2 × 10 mL). Purification was effected by
flash column chromatography (EtOAc-hexane 1:10) to give
compound 10 as a colorless oil (1.83 g, 92%): [R]25D ) -39.0 (c
) 1.0, CH2Cl2); IR (neat) ν ) 3381, 2956, 2931, 1697, 1626,
(1R)-2-en d o-[(3R,4S,5S)-3-Meth oxy-5-m eth yl-4-(N-m e-
t h yla m in o)h ep t a n oyl]-2-exo-t r im et h ylsilyloxy-1,7,7-t r i-
m eth ylbicyclo[2.2.1]h ep ta n e (13). A round-bottom flask
containing a mixture of 12 (0.457 g, 0.835 mmol) and Pd/C
(10% Pd, 0.089 g, 0.08 mmol) in EtOAc (4 mL) was stirred
overnight at 25 °C under a balloon full of H2. Then the flask
was purged with N2, and the mixture was filtered through a
short column of Celite and washed well with EtOAc. The
solvent was removed under reduced pressure to afford product
1
1454, 1083; H NMR (200 MHz, DMSO-d6, 90 °C) δ ) 7.30-
13 (0.342 g, 99%): mp 70-71 °C; [R]25 ) +5.9 (c ) 1.0, CH2-
D
7.12 (m, 10H), 4.92 (m, 1H), 4.72 (s, 1H), 4.45 (m, 1H), 3.93
(d, J ) 12.1 Hz, 1H), 3.77 (d, J ) 6.2 Hz, 1H), 3.73 (d, J )
12.1 Hz, 1H), 3.27 (dd, J ) 5.9, 17.9, 1H), 3.15 (dd, J ) 15.4,
4.0 Hz, 1H), 2.90 (m, 1H), 2.90 (s, 3H), 2.42 (dd, J ) 3.7, 17.6
Hz, 1H), 2.25 (d, J ) 12.5 Hz, 1H), 1.89-1.48 (m, 4H), 1.25
(m, 1H), 1.14-0.74 (m, 2H), 1.11 (s, 3H), 0.95 (s, 3H), 0.92 (s,
9H), 0.86 (d, J ) 5.5 Hz, 3H), 0.80 (s, 3H), 0.76 (d, J ) 6.6 Hz,
3H), 0.14 (s, 3H), 0.06 (s, 3H); 13C NMR (50 MHz, CDCl3) δ of
major rotamer ) 211.1, 172.6, 138.1, 137.5, 128.7, 128.4, 128.2,
127.9, 127.7, 127.3, 126.3, 87.7, 81.4, 72.0, 70.4, 58.0, 51.8, 51.0,
48.4, 45.1, 41.9, 31.4, 30.6, 30.3, 26.2, 26.0, 25.9, 25.7, 21.0,
20.7, 18.7, 18.4, 17.9, 11.1, -3.7, -4.7; MS (ESI, m/z) calcd
for C40H62NO5Si (M + H+) 664.44, found 664.5.
Cl2); IR (neat) ν ) 2958, 2933, 2876, 1252, 1088, 841; 1H NMR
(200 MHz, CDCl3) δ ) 3.91 (m, 1H), 3.29 (s, 3H), 3.19 (dd, J )
9.5, 19.0 Hz, 1H), 2.53 (d, J ) 11.7 Hz, 1H), 2.46 (m, 1H), 2.44
(s, 3H), 2.22 (dd, J ) 2.3, 12.0 Hz, 1H), 1.76-0.64 (m, 6H,
complex), 1.00 (s, 3H), 0.95 (s, 3H), 0.88 (t, J ) 7.3 Hz, 3H),
0.84 (d, J ) 7.3 Hz, 3H), 0.77 (s, 3H), 0.06 (s, 9H); 13C NMR
(50 MHz, CDCl3) δ ) 208.6, 90.5, 76.3, 65.0, 57.5, 51.7, 50.8,
45.2, 40.3, 39.9, 35.9, 29.8, 26.0, 25.8, 20.9, 20.3, 16.0, 11.9,
11.3, 1.8, 1.7, 1.0. Anal. Calcd for C23H45NO3Si (411.69): C,
67.10; H, 11.02; N, 3.40. Found: C, 66.98; H, 11.15; N, 3.62.
(1R)-2-en d o-[(3R,4S,5S)-4-(N-((2S)-N-Ben zyloxyca r bo-
n ylam in o-3-m eth ylbu tan oyl)-N-m eth ylam in o)-3-m eth oxy-
4132 J . Org. Chem., Vol. 69, No. 12, 2004

Total Synthesis of Hapalosin
5-m eth ylh eptan oyl]-2-exo-tr im eth ylsilyloxy-1,7,7-tr im eth -
ylbicyclo[2.2.1]h ep ta n e (15). Diisopropylethylamine (0.118
mL, 0.68 mmol) was added to a solution of N-Cbz-L-valine 14
(0.1005 g, 0.4 mmol), 13 (0.0825 g, 0.2 mmol), and bromotris-
(dimethylamino)phosphonium hexafluorophosphate (BroP)22
(0.1164 g, 0.3 mmol) in CH2Cl2 (2 mL), and the resulting
mixture was shielded from light and stirred at 0 °C for 10 min
and then at room temperature for 24 h. The mixture was
washed with 1 M aqueous KHSO4 (15 mL), and the aqueous
layer was extracted with CH2Cl2 (3 × 20 mL). The combined
organic extracts were washed with water (25 mL), dried over
MgSO4, and filtered, and the solvent was removed under
reduced pressure. The crude product was purified by column
chromatography (eluant: ethyl acetate/hexane 1:35): yield
saturated solution of NaHCO3, and the aqueous layer was
extracted with CH2Cl2 (3 × 15 mL). The organic layer was
dried over MgSO4 and filtered and the solvent removed under
reduced pressure. The crude product was used in the next
reaction without further purification. A solution of cerium
ammonium nitrate (CAN) (1.28 g, 2.3 mmol) in water (5 mL)
was added dropwise to a solution of the above crude in
acetonitrile (9 mL) at 0 °C, and the mixture was stirred at
the same temperature for 5 min. Then water (6 mL) was
added, and the mixture was extracted with CH2Cl2 (2 × 15
mL). The combined organic extracts were dried over MgSO4
and filtered, and the solvent was removed under reduced
pressure. The crude product was purified by column chroma-
tography (eluant: ethyl acetate/hexane 1:10) to afford (1R)-
(+)-camphor in the first fractions and compound 17 in the
0.104 g, 81%; [R]25 ) +2.0 (c ) 1.0, CH2Cl2); IR (neat) ν )
D
1
subsequent fractions (0.263 g, 63%): mp 134-135 °C; [R]25
2958, 1712, 1637, 1251, 842; H NMR (200 MHz, DMSO-d6,
D
90 °C) δ ) 7.34 (sb, 5H), 6.79 (d, J ) 8.8 Hz, 1H), 5.10 (d, J )
12.4 Hz, 1H), 5.01 (d, J ) 12.4 Hz, 1H), 4.60 (m, 1H), 4.32
(dd, J ) 7.3, 8.8 Hz, 1H) 4.04 (m, 1H), 3.27 (s, 3H), 3.11 (dd,
J ) 9.5, 18.3 Hz, 1H), 2.97 (s, 3H), 2.50 (m, 1H), 2.29 (dd, J )
1.5, 18.3 Hz, 1H), 2.10 (m, 1H), 1.79 (m, 3H), 1.59 (m, 1H),
1.29 (m, 2H), 1.06-0.75 (m, 3H, complex), 1.02 (s, 3H), 0.98
) -36.0 (c ) 1.0, CH2Cl2); IR (neat) ν ) 3400, 2969, 2933,
1
1702, 1630, 1379; H NMR (200 MHz, DMSO-d6, 90 °C) δ )
7.62 (d, J ) 8.8 Hz, 1H), 7.34 (sb, 5H), 6.83 (d, J ) 8.8 Hz,
1H), 5.91 (sb, 1H), 5.04 (s, 2H), 4.60 (m, 1H), 4.48 (m, 1H),
3.94 (m, 2H), 3.27 (s, 3H), 2.93 (s, 3H), 2.60-1.62 (m, 5H,
complex), 1.30 (m, 2H), 0.80 (m, 18H, complex); 13C NMR (50
MHz, CDCl3) δ both rotamers ) 173.1, 171.6, 156.6, 137.8,
137.7, 129.6, 128.9, 128.4, 128.3, 127.7, 126.0, 79.2, 66.1, 60.3,
57.7, 54.8, 33.3, 32.3, 31.3, 31.0, 26.2, 21.9, 20.0, 19.8, 19.3,
18.9, 16.6, 11.4. Anal. Calcd for C28H45N3O7 (535.67): C, 62.78;
H, 8.47; N, 7.84. Found: C, 63.02; H, 8.72; N, 6.59.
(s, 3H), 0.90 (s, 9H), 0.85 (s, 3H), 0.80 (t, J ) 7.0 Hz, 3H); 13
C
NMR (50 MHz, CDCl3) δ both rotamers ) 208.0, 173.8, 156.9,
138.0, 129.0, 128.4, 128.1, 90.6, 76.6, 65.9, 58.2, 57.2, 51.9, 51.2,
45.4, 32.4, 30.5, 30.2, 26.3, 26.1, 21.6, 20.9, 19.8, 19.1, 16.4,
11.8, 10.9, 2.4, 2.2.
(1R)-2-en d o-[(3R,4S,5S)-4-(N-((2S)-((2S)-N-b en zyloxy-
ca r bon yla m in o-3-m eth ylbu ta n oyl)-3-m eth ylbu ta n oyl)-N-
m eth yla m in o)-3-m eth oxy-5-m eth ylh ep ta n oyl]-2-exo-tr i-
m eth ylsilyloxy-1,7,7-tr im eth ylbicyclo[2.2.1]h ep ta n e (16).
A round-bottom flask containing a mixture of 15 (0.0594 g,
0.092 mmol) and Pd/C (10% Pd, 0.0098 g, 0.0092 mmol) in
EtOAc (0.5 mL) was stirred overnight at 25 °C under a balloon
full of H2. Then the flask was purged with N2, and the mixture
was filtered through a short column of Celite and washed well
with EtOAc. The solvent was removed under reduced pressure
to afford a product (0.0465 g, 99%) which was used in the next
reaction without further purification.
Ben zyl (2S,3R)-3-((3R,4S)-4-N-((S)-2-Ben zyloxy-3-m e-
th ylbu ta n oyl)-N-m eth yla m in o-3-ter t-bu tyld im eth ylsilyl-
oxy-5-p h en ylp en ta n oyloxy)-2-m eth yld eca n oa te (19). Ox-
alyl chloride (0.30 mL, 4.5 mmol) was added dropwise to a
solution of 11 (0.79 g, 1.5 mmol) in CH2Cl2 (6 mL) cooled to 0
°C. The mixture was stirred at room temperature for 3 h, and
then the solvent and excess oxalyl chloride were removed
under reduced pressure and the crude product was used in
the next reaction as is. A solution of the acid chloride (1.5
mmol) in CH2Cl2 (1.5 mL) was added to a cooled (0 °C) solution
of benzyl (2S,3R)-3-hydroxy-2-methyldecanoate 187b (0.44 g,
1.5 mmol) and DMAP (0.46 g, 3.75 mmol) in CH2Cl2 (7.5 mL).
The resulting solution was stirred at room temperature for 3
h, and then it was washed with 1 N HCl (3 × 10 mL) and
with a saturated solution of NaHCO3 (2 × 10 mL). The organic
layer was dried over MgSO4 and filtered and the solvent
removed under reduced pressure. The residue was purified by
column chromatography (ethyl acetate/hexane 1:50) to afford
Diisopropylethylamine (0.945 mL, 5.44 mmol) was added
to a solution of N-Cbz-L-valine 14 (0.8041 g, 3.2 mmol), the
above product (0.8142 g, 1.6 mmol), and bromotris(dimethyl-
amino)phosphonium hexafluorophosphate (BroP) (0.9313 g, 2.4
mmol) in CH2Cl2 (18 mL), and the resulting mixture was
shielded from light and stirred at 0 °C for 10 min and then at
room temperature for 24 h. The mixture was washed with 1
M aqueous KHSO4 (20 mL), and the aqueous layer was
extracted with CH2Cl2 (3 × 20 mL). The combined organic
extracts were washed with water (25 mL), dried over MgSO4,
and filtered, and the solvent was removed under reduced
pressure. The crude product was purified by column chroma-
tography (eluant: ethyl acetate/hexane 1:5): yield 0.7143 g,
compound 19 as an oil (0.96 g, 80%): [R]25 ) -37.0 (c ) 1.0,
D
CH2Cl2); IR (neat) ν ) 2956, 2928, 1735, 1653, 1497, 1456, 836;
1H NMR (200 MHz, CDCl3) δ ) 7.34-7.00 (m, 15H), 5.11 (m,
1H), 5.03 (s, 2H), 4.40 (m, 1H), 4.13 (d, J ) 11.4 Hz, 1H), 3.57
(d, J ) 7.0 Hz, 1H), 3.57 (m, 1H), 3.27 (dd, J ) 7.0, 14.7 Hz,
1H), 2.75 (s, 3H), 2.75-2.49 (m, 5H), 1.82 (m, 1H), 1.49 (m,
2H), 1.20 (m, 10H), 1.08 (d, J ) 7.3 Hz, 3H), 0.87 (m, 6H),
0.87 (s, 9H), 0.67 (d, J ) 7.0 Hz, 3H), 0.11 (s, 3H), 0.05 (s,
3H); 13C NMR (50 MHz, CDCl3) δ of major rotamer ) 173.4,
171.9, 171.0, 138.4, 138.0, 135.8, 129.0, 128.7, 128.5, 128.4,
128.2, 128.0, 127.7, 127.6, 127.3, 126.4, 82.5, 74.7, 70.5, 70.0,
66.4, 43.0, 40.3, 34.2, 32.0, 31.8, 30.3, 29.4, 29.2, 26.0, 25.5,
22.7, 19.2, 18.1, 14.1, 12.3, -3.9, -4.6; MS (ESI, m/z) calcd
for C48H72NO7Si (M + H+) 802.51, found 802.5.
60%; mp 178-179 °C; [R]25 ) -15.0 (c ) 1.0, CH2Cl2); IR
D
1
(neat) ν ) 3283, 2959, 2873, 1712, 1631, 1245; H NMR (200
MHz, DMSO-d6, 90 °C) δ ) 7.63 (d, J ) 8.8 Hz, 1H), 7.36 (m,
5H), 6.83 (d, J ) 8.8 Hz, 1H), 5.05 (s, 2H), 4.63 (m, 2H), 4.01
(m, 2H), 3.27 (s, 3H), 3.12 (dd, J ) 9.5, 18.3 Hz, 1H), 2.97 (s,
3H), 2.50 (m, 1H), 2.10 (m, 2H), 1.80 (m, 2H), 1.60 (m, 1H),
1.27 (m, 2H), 1.07-0.78 (m, 4H, complex), 0.09 (s, 9H); 13C
NMR (50 MHz, CDCl3) δ both rotamers ) 207.5, 172.8, 170.9,
156.1, 136.3, 128.3, 127.9, 90.3, 75.5, 66.8, 60.2, 57.8, 55.9, 55.8,
54.3, 54.4, 50.8, 45.2, 40.1, 39.6, 32.7, 31.5, 31.2, 30.1, 25.8,
20.9, 20.3, 19.4, 19.1, 17.8, 17.6, 15.5, 11.4, 10.4, 1.5. Anal.
Calcd for C41H69N3O7Si (744.09): C, 66.18; H, 9.35; N, 5.65.
Found: C, 65.86; H, 9.48; N, 5.76.
(2S,3R)-3-((3R,4S)-3-ter t-Bu t yld im et h ylsilyloxy-4-N-
((S)-2-h ydr oxy-3-m eth ylbu tan oyl)-N-m eth ylam in o-5-ph en -
ylp en ta n oyloxy)-2-m eth yld eca n oic Acid (20). A round-
bottom flask containing a mixture of 19 (0.80 g, 1 mmol) and
Pd/C (10% Pd, 0.106 g, 0.1 mmol) in EtOAc (2 mL) was stirred
for 1 h at 25 °C under a balloon full of H2. Then the flask was
purged with N2 and the mixture was filtered through a short
column of Celite and washed well with EtOAc. The solvent
was removed under reduced pressure to afford product 20 as
an oil (0.61 g, 98%): [R]25D ) -20.5 (c ) 1.0, CH2Cl2); IR (neat)
(1R)-2-en d o-[(3R,4S,5S)-4-(N-((2S)-((2S)-N-Ben zyloxy-
ca r bon yla m in o-3-m eth ylbu ta n oyl)-3-m eth ylbu ta n oyl)-N-
m eth yla m in o)-3-m eth oxy-5-m eth ylh ep ta n oic Acid (17).
HF (48% aqueous solution) (1.5 mL) was added to a solution
of 16 (0.5778 g, 0.78 mmol) in methanol (6 mL) at room
temperature, and the mixture was stirred for 6 h at the same
1
ν ) 3432, 2956, 2929, 1737, 1640, 1464, 1083, 837; H NMR
(500 MHz, CDCl3) (data of both rotamers unless otherwise
temperature. Then, the mixture was neutralized with
a
noted) δ ) 7.25-7.10 (m, 5H), 5.33 (m, 1H), 4.35 (m, 1H,
J . Org. Chem, Vol. 69, No. 12, 2004 4133

Palomo et al.
corresponding to single rotamer), 3.97 (m, 1H, single), 3.41 (d,
J ) 7.3 Hz, 1H, single), 3.32 (dd, J ) 14.1, 2.4 Hz, 1H, single),
3.23 (dd, J ) 13.8, 3.4 Hz, 1H, single), 3.10 (dd, J ) 8.2, 18.7
Hz, 1H, single), 2.89 (s, 3H, single), 2.77-2.60 (m, 1H both,
4H single), 2.54-2.43 (m, 1H both, 1H single), 1.63 (m, 1H
both, 1H single), 1.50 (m, 1H both, 2H single), 1.28 (m, 12H
both, 1H single), 1.16 (d, J ) 6.8 Hz, 3H, single), 1.10 (d, J )
6.8 Hz, 3H, single), 0.98-0.83 (m, 4H both, 6H single), 0.96
(s, 9H, single), 0.94 (s, 9H, single), 0.65 (d, J ) 6.8 Hz, 3H,
single), 0.18 (d, J ) 6.8 Hz, 3H, single), 0.17 (s, 3H, single),
0.14 (s, 3H, single), 0.12 (s, 3H, single), 0.08 (s, 3H, single);
13C NMR (50 MHz, CDCl3) δ of major rotamer ) 177.7, 174.4,
170.5, 137.8, 129.0, 128.7, 128.3, 126.3, 74.4, 72.6, 69.5, 64.6,
42.7, 40.3, 34.2, 31.7, 30.4, 29.1, 25.9, 25.8, 22.6, 20.0, 18.0,
were dried over MgSO4 and filtered, and the solvent was
removed under vacuum. The residue was purified by column
chromatography (ethyl acetate/hexane 1:15) to afford hapalosin
1 as a colorless oil that solidified on standing (0.124 g, 54%).
Data of the mixture of two conformers: [R]25 ) -40 (c ) 1.0,
D
CH2Cl2); IR (neat) ν ) 3411, 2959, 1731, 1631, 1496, 1456,
1
1151; H NMR (500 MHz, CDCl3) δ ) 7.34 (dd, J ) 7.0, 7.7
Hz, 2H), 7.26-7.19 (m, 3H), 5.13 (m, 1H), 4.32 (d, J ) 8.4 Hz,
1H), 3.86 (m, 1H), 3.70 (dt, J ) 8.8, 2.5 Hz, 1H), 3.41 (dd, J )
13.9, 2.5, 1H), 3.24 (m, 1H), 2.93 (dd, J ) 5.3, 17.9 Hz, 1H),
2.86 (s, 3H), 2.65 (m, 1H), 2.62 (m, 1H), 2.02 (m, 1H), 1.92 (m,
1H), 1.62 (m, 1H), 1.40-1.20 (mb, 10H), 1.18 (d, J ) 6.9 Hz,
3H), 0.89 (m, 3H), 0.56 (d, J ) 6.9 Hz, 3H), 0.24 (d, J ) 6.9
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ ) 172.6, 171.7, 170.4,
170.0, 168.6, 168.5, 137.7, 137.3, 129.1, 128.9, 128.7, 128.2,
126.9, 126.2, 82.9, 76.5, 74.8, 73.8, 70.1, 61.3, 59.0, 40.9, 40.7,
40.3, 37.3,36.2, 35.3, 31.7, 31.7, 30.6, 29.4, 29.2, 29.1, 28.9, 28.1,
26.0, 25.2, 22.6, 19.6, 18.3, 17.6, 16.6, 14.1, 12.1, 10.4; MS (ESI,
m/z) calcd for C28H44NO6 (M + H+) 490.32, found 490.3.
15.0, 14.1, 11.5, -4.0, -4.8; MS (ESI, m/z) calcd for C34H59
-
NO7Si (M - H+) 620.40, found 620.3.
Ha p a losin (1). EDC (0.26 g, 1.4 mmol), di-2-pyridyl ketone
oxime (0.19 g, 1 mmol), and DMAP (1 mg, 0.01 mmol) were
added successively to a solution of the crude acid 20 (0.62 g, 1
mmol) in CH2Cl2 (0.5 mL) at room temperature, and the
mixture was stirred for 12 h at the same temperature. Then,
CH2Cl2 (15 mL) was added, and the mixture was washed with
1 M KHSO4 (10 mL) and with water (2 × 10 mL). The organic
layer was dried over MgSO4 and filtered and the solvent
removed under reduced pressure. The crude product was used
in the next reaction without further purification. Yield crude:
0.74 g, 93%. A solution of the dipyridyl O-acyl oxime (0.36 g,
0.47 mmol) and Cu(TfO)2 (0.18 g, 0.50 mmol) in acetonitrile
(460 mL) was stirred at reflux for 14 h. The solvent was then
removed under reduced pressure, and after addition of CH2-
Cl2 (15 mL), the mixture was washed with water (3 × 10 mL).
The organic layer was dried over MgSO4 and filtered and the
solvent removed under reduced pressure. The crude was
dissolved in THF (10 mL), and then HF/pyridine complex
(Aldrich) (2 mL) was added dropwise at room temperature and
the mixture was stirred for 4 h. Then a saturated solution of
NaHCO3 was added to remove excess acid, and the mixture
was extracted with CH2Cl2 (2 × 15 mL). The organic extracts
Ack n ow led gm en t. This work was financially sup-
ported by The University of the Basque Country (EHU/
UPV) and Ministerio de Ciencia y Tecnologia (Spain)
and in part by Gobierno Vasco (Departamento de
Industria, Comercio y Turismo; programa ETORTEK).
Grants to R.P. from EHU/UPV, P.B. from Ministerio de
Educacio´n Cultura y Deporte, and M.T. from Gobierno
de Navarra are acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures, characterization data for compounds 5c,d ,f-h , 1H and
13C NMR spectra of compounds 1, 5a , 6, 8-13, 15-17, 19, 20,
and X-ray crystallographic data for compounds 13 and II in
CIF format. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O0497499
4134 J . Org. Chem., Vol. 69, No. 12, 2004