The total synthesis of (-)-amathaspiramide F

Article abstract of DOI:10.1002/1521-3773(20021202)41:23<4556::AID-ANIE4556>3.0.CO;2-E

Breaking the cis rule: L-Proline and not as expected D-proline led to (-)-amathaspiramide F with the correct configuration in a short sequence of steps (see retrosynthetic scheme). This synthesis features an exception to the principle of self-regeneration

Full text of DOI:10.1002/1521-3773(20021202)41:23<4556::AID-ANIE4556>3.0.CO;2-E

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[Cu3(H2L3)(NO3)](NO3)(dmf)4¥H2O (2¥4dmf¥H2O).
A
mixture of
173, 181; c) S. S. Tandon, L. K. Thompson, J. N. Bridson, V. McKee,
A. J. Downard, Inorg. Chem. 1992, 31, 4635.
[5] S. Goetz, Ph.D Thesis, Loughborough University (UK), 2002.
[6] a) V. Bˆhmer, Angew. Chem. 1995, 107, 785; Angew. Chem. Int. Ed.
Engl. 1995, 34, 713; b) D. C. Gutsche, Calixarenes revisited, The Royal
Society of Chemistry, Cambridge, 1998.
Cu(NO3)2¥6H2O (0.321 g, 1.08 mmol) and dhtmb (0.20 g, 0.543 mmol) in
dry ethanol (80 mL) were heated to reflux for 10 min and a solution of 1,3-
diaminopropan-2-ol (0.052 g, 0.543 mmol) in dry methanol (20 mL) added
dropwise. The emerald green solution darkened as reflux was continued for
2 h. the mixture was filtered, cooled, and concentrated under vacuum
where upon
a
green solid precipitated (analyzed as [Cu4(H4L)-
[7] a) F. Hamada, K. D. Robinson, G. W. Orr, J. L. Atwood, Supramol.
Chem. 1993, 2, 19; b) S. E. J. Bell, J.K. Browne, V. McKee, M. A.
McKervey, J. F. Malone, M. O©Leary, A. Walker, F. Arnaud Neu, O.
Boulangeot, O. Mauprivez, M.-J. Schwing-Weill, J. Org. Chem. 1998,
63, 489; c) G. Guillemot, E. Solari, C. Floriani, N. Re, C. Rizzoli,
Organometallics 2000, 19, 5218.
[8] a) A. Gelasco, M. L. Kirk, J. W. Kampf, V. L. Pecoraro, Inorg.Chem.
1997, 36, 1829; b) P. E. Kruger, B. Moubaraki, G. D. Fallon, K. S.
Murray, J. Chem. Soc. Dalton Trans. 2000, 713; c) Y. Nishida, M.
Takeuchi, K. Takahashi, S. Kida, Chem. Lett. 1985, 631, 631.
[9] B. Dhawan, C. D. Gutsche, J. Org. Chem. 1983, 48, 1536.
[10] P. v. d. Sluis, A. L. Spek, Acta Cryst. 1990, A46, 194.
[11] G. M. Sheldrick, SHELXTL version 5.1, Bruker-AXS, Madison WI,
1998.
(NO3)(OH)2(H2O)4]). This complex was dissolved in DMF and the color
changed to brown; crystals of the trinuclear complex 2¥3dmf were obtained
in 40% yield by diffusion of diethyl ether into the solution. Elemental
analysis calcd (%) for 2¥4dmf¥H2O: C 51.8, H 6.4, N9.4; found: C 52.1, H
6.5, N9.4. Crystal dimensions: 0.45 î 0.24 î 0.04 mm 3, monoclinic, space
group P21/c, a ¼ 17.234(1), b ¼ 22.130(2), c ¼ 17.658(1) ä, b ¼ 103.488(1)8,
V¼ 6549.0(8) ä3, 1calcd ¼ 1.395 Mgmꢀ3. 46309 reflections, 11521 independ-
ent (Rint ¼ 0.0424), m ¼ 1.036 mmꢀ1, Tmax ¼ 1.000, Tmin ¼ 0.885; 859 least-
squares parameters R1 ¼ 0.0646 wR2 ¼ 0.1638 (2s data).
[Cu4(H2L3)(OH)2(sol)2](NO3)2 (3¥2H2O where sol ¼ water or ethanol). A
mixture of Cu(NO3)2¥6H2O (0.16 g, 0.543 mmol) and dhtmb (0.20 g,
0.543 mmol) in dry ethanol (70 mL) was heated to reflux for 10 min and
a solution of 1,3-diaminopropan-2-ol (0.052 g, 0.543 mmol) in dry methanol
(20 mL) added dropwise. The solution changed to emerald green and
darkened as reflux was continued for 1 h. The solution was cooled, filtered,
and evaporated to dryness. The residue was then dissolved in dichloro-
methane, filtered, and evaporated again before being dissolved in ethanol.
Green [Cu4(H2L3)(OH)2(H2O)2](NO3)2¥2H2O was obtained from this
solution in 79% yield. Elemental analysis calcd (%) for 3¥2H2O: C 47.1,
H 5.6, N6.3; found: C 47.1, H 5.5, N6.3. Crystals of [Cu 4(H2L3)(OH)2-
(H2O)(EtOH)](NO3)2¥2EtOH¥H2O (3¥2EtOH¥H2O) were obtained by
slow evaporation of a solution of 3¥2H2O in an ethanol/benzene/petroleum
ether mixture. Crystal dimensions: 0.31 î 0.13 î 0.04 mm3, monoclinic,
space group P21/c, a ¼ 11.867(2), b ¼ 14.125(3), c ¼ 41.220(7) ä, b ¼
93.406(3)8, V¼ 6897(2) ä3, 1calcd ¼ 0.352 Mgmꢀ3. 47670 reflections, 12095
independent (Rint ¼ 0.0902), m ¼ 1.285 mmꢀ1, Tmax ¼ 1.000, Tmin ¼ 0.766; 696
least-squares parameters R1 ¼ 0.0763 wR2 ¼ 0.21.19 (2s data). The unco-
ordinated solvate molecules and nitrate ions were highly disordered and
were treated using the SQUEEZE program[10] (see the Supporting
Information).
The Total Synthesis of
(ꢀ)-Amathaspiramide F**
Chambers C. Hughes and Dirk Trauner*
The amathaspiramides A F (1 6) are a family of marine
alkaloids recently isolated from a New Zealand collection of
the bryozoan Amathia wilsoni.[1,2] Marked by a dense array of
polar functionality, the natural products feature a novel
X-ray data were collected at 150(2) K on
a Bruker SMART 1000
diffractometer using MoKa radiation (l ¼ 0.71073 ä) to 2qmax of 258. The
structures were solved by direct methods and refined on F2 using all the
data.[11] Non-hydrogen atoms were refined with anisotropic ADPs and
hydrogen atoms attached to full-occupancy carbon atoms were inserted at
calculated positions. Details concerning treatment of disorders and of
hydrogen atoms not bonded to carbon atoms are described in the
Supporting Information. CCDC 190246.(1¥1.6Et2O¥EtOH) CCDC 190247
(2¥3dmf), and CCDC 190248 (1¥2H2O) contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crys-
tallographic Data Centre, 12 Union Road, Cambridge CB21EZ, UK; fax:
(þ 44)1223-336-033; or deposit@ccdc.cam.ac.uk).
Received: August 6, 2002 [Z19906]
[1] a) R. C. Long, D. N. Hendrickson, J. Am. Chem. Soc. 1983, 105, 1513;
b) H. Okawa, J. Nishio, M. Ohba, M. Tadokoro, N. Matsumoto, M.
Koikawa, S. Kida, D. E. Fenton, Inorg. Chem. 1993, 32, 2949; c) M.
Yonemura, N. Usuki, Y. Nakamura, M. Ohba, H. Okawa, J. Chem.
Soc. Dalton Trans. 2000, 3624; d) A. Atkins, D. Black, A. J. Blake, A.
Marin-Becerra, S. Parsons, L. Ruiz-Ramirez, M. Schrˆder, Chem.
Commun. 1996, 457.
[2] a) A. Hori, M. Yonemura, M. Ohba, H. Okawa, Bull. Chem. Soc. Jpn.
2001, 74, 495; b) M. J. Grannas, B. F. Hoskins, R. Robson, Inorg.
Chem. 1994, 33, 1071; c) K. K. Nanda, S. Mohanta, U. Florke, S. K.
Dutta, K. Nag, J. Chem. Soc. Dalton Trans. 1995,3831; d) J. McCrea, V.
McKee, T. Metcalfe, S. S. Tandon, J. Wikaira, Inorg. Chim. Acta 2000,
297, 220.
[*] Prof. D. Trauner, C. C. Hughes
Center for New Directions in Organic Synthesis
Department of Chemistry
University of California, Berkeley
Berkeley, CA 94720-1460 (USA)
Fax : (þ 1)510-643-9480
E-mail: trauner@cchem.berkeley.edu
[3] a) V. McKee, S. S. Tandon, J. Chem. Soc. Dalton Trans. 1991 221;
b) P. E. Kruger, V. McKee, Chem. Commun. 1997 1341; c) S. Cromie,
F. Launay, V. McKee, Chem. Commun. 2001, 1918.
[4] a) S. S. Tandon, V. McKee, J. Chem. Soc. Dalton Trans. 1989 19;
b) A. J. Downard, V. McKee, S. S. Tandon, Inorg. Chim. Acta 1990,
[**] The Center for New Directions in Organic Synthesis is supported by
Bristol-Myers Squibb as a Sponsoring Member and Novartis as a
Supporting Member. We also thank Eli Lilly for a pre-doctoral
fellowship (C.C.H.) and Dr. Frederick J. Hollander and Dr. Allen G.
Oliver (Berkeley) for crystal structure determinations.
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spirobicyclic core consisting of pyrrolidine and pyrrolidinone
rings and an unusual dibromomethoxyphenyl ring. Their
structures and absolute configurations were established by
anomalous X-ray diffraction of amathaspiramide F and ex-
tensive NMR studies. Though several of the amathaspira-
mides are moderately cytotoxic or show antiviral and anti-
biotic properties, they attracted our attention mostly due to
their intriguing molecular architecture. We now report the
first total synthesis of a member of this family, amathaspir-
amide F (6).
Because of the relatively high cost of d-proline, however, we
decided to first use its cheaper enantiomer, aiming at a
synthesis of nonnatural (þ)-amathaspiramide F. Our synthesis
therefore started with the known N,N-acetal 11,[6] the
alkylation of which has not been previously reported
(Scheme 2). Initial attempts to alkylate 11 were unsuccessful
since the a position proved difficult to deprotonate. Fortu-
Our synthetic program provided an opportunity to show-
case Seebach×s concept of ™self-regeneration of stereochem-
istry (SRS)∫,[3] a method for the asymmetric a alkylation of
amino acids that has been widely exploited in the preparation
of novel amino acids and peptidomimetics and in the total
synthesis of several natural products.[4]
Retrosynthetically, disconnection of the N-acyl hemiaminal
function in amathaspiramide F (6) leads to the amino
aldehyde 7, which can be traced back to the nitroalkyl
compound 8 via Nef reaction and engagement of the aldehyde
and amide function in a cyclic acetal (Scheme 1). We reasoned
that this key intermediate could be derived from N,N-acetal 9
Scheme 2. Reagents and conditions: a) 1. tBuLi, HMPA, THF, ꢀ788C!
RT; 2. TBSCl, 08C; b) 1. 10, ꢀ788C; 2. MgBr2¥OEt2, ꢀ788C!RT, 72 %,
10:1 (13a:13b) mixture of diastereomers. HMPA ¼ hexamethylphosphor-
amide, TBSCl ¼ tert-butyldimethysilyl chloride.
nately, in the presence of HMPA, the desired enolate could be
cleanly generated using tert-butyllithium. Simple addition of
nitro olefin 10[7] to this enolate, however, resulted in the
formation of a complex mixture with no detectable trace of
the desired product. This difficult conjugate addition was
finally realized when the silyl ketene acetal 12 was generated
in situ and reacted with the nitro olefin in the presence of
MgBr2¥OEt2.[8] A 10:1 mixture of diastereomers 13a and 13b
was thus obtained (see Experimental Section).
To our surprise, however, the two diastereomers 13a and
13b turned out to be both S-configured at the newly formed
quaternary center. This fortuitous violation of the cis rule was
confirmed by an X-ray analysis of the major diastereomer 13a
(Figure 1).[9,10] Remarkably, both the quaternary and the
benzylic stereocenter in 13a correspond to the natural
amathaspiramide series.
According to literature precedence[3b] and our own calcu-
lations, the bicyclic silyl ketene acetal 12 adopts a cup-shaped
conformation wherein the two nitrogen atoms are pyrami-
dalized and the tert-butyl group resides on the convex side of
the bicycle (Scheme 3). Conventionally, the alkylation would
proceed from this side as well. However, in 12 the bulky TBS
substituent is also oriented towards the convex side of the
diazabicyclo[3.3.0]octene framework, considerably crowding
the corresponding diastereoface of the nucleophilic double
bond. Apart from this ground state argument, unfavorable
torsional interactions between the N-methyl group and the
OTBS substituent may occur in a transition state leading to
the cis product (14b). Hence the alkylation takes place from
Scheme 1. Retrosynthetic analysis of amathaspiramide F.
by conjugate addition of its lithium enolate to the nitrostyrene
derivative 10.[5] The N-methyl moiety of the final product
would thus be introduced at an early stage of the synthesis.
Following ample precedence given by Seebach and others, the
alkylation of 9 should proceed under retention of configu-
ration. In other words, the substituent replacing the bridge-
head hydrogen atom would reside cis with respect to the tert-
butyl group (™cis rule∫). We were not particularly concerned
about the stereochemical outcome of the conjugate addition
with respect to the benzylic stereocenter at C9. Given its
position next to a masked carbonyl group, the aryl ring would
probably adopt the thermodynamically most stable config-
uration in the final product.
According to this retrosynthetic analysis, the synthesis of
natural 5S-configured amathaspiramide F (or C) would re-
quire an acetal derived from d-proline as starting material.
Angew. Chem. Int. Ed. 2002, 41, No. 23
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Figure 1. Molecular structure of 13a.
Scheme 5. Reagents and conditions: a) 4m H2SO4, THF, RT, 86%;
b) 1. TFAA, py, CH2Cl2, 08C; 2. MeOH, 08C!RT, 98%; c) SnCl2, PhSH,
Scheme 3. Stereochemical rationale for the preferred formation of dia-
stereomer 13a.
Et3N, MeCN, RT, 85%; d) IBX, THF, DMSO, RT, 65%; e) LiBH , THF,
4
08C!RT, 80 %. TFAA ¼ trifluoroacetic anhydride, IBX ¼ 1-hydroxy-1,2-
benziodoxol-3(1H)-one-1-oxide.
the opposite side, via 14a, resulting in trans substitution with
inversion of the stereocenter (Scheme 3). The high simple
diastereoselection (10:1 in favor of 13a) can be explained by
invoking an open transition state with the dibrominated
phenyl ring oriented away from the bicyclic component.
Supporting this stereochemical rationale, the well-prece-
dented alkylation of N,O-acetal 15[3a] afforded the expected
5R-cis product 17[10] as the only isolated diastereomer
(Scheme 4). In this case, the reaction presumably proceeds
through the open transition state 16.
Having quickly assembled the carbon skeleton of the
amathaspiramides, we turned our attention toward the
formation of the missing heterocyclic ring. The completion
of the synthesis required cleavage of the acetal, conversion of
the primary nitro group to an aldehyde via a Nef reaction[11]
(or its equivalent), and subsequent cyclization to yield
amathaspiramide F. Though the hydrolysis of the N,N-acetal
was achieved without difficulties (Scheme 5), direct imple-
mentation of the Nef reaction proved problematic. Starting
from either acetal 13a or its hydrolysis product 18, no
aldehyde or cyclized product could be obtained under a
variety of hydrolytic or oxidative conditions.[12]
Since all attempts to convert the nitro group into the
aldehyde in the presence of a free secondary amine failed, we
reluctantly resorted to protecting group manipulations. Re-
cently, the trifluoroacetyl function has emerged as a useful
protecting group for sterically hindered amines,[13] for exam-
ple, those attached to a quaternary center. Accordingly, 18
was treated with trifluoroacetic anhydride to afford 19
(Scheme 5). With the basic nitrogen thus protected, 19 could
be efficiently converted to oxime 20 following a protocol
described by Bartra et al.[14] Hydrolysis of the oxime with
concomitant cyclization was then achieved with a hypervalent
iodine reagent (IBX)[15] to afford N-trifluoroacetyl amathas-
piramide F (21).[16] Notably, no formation of the diastereomer
corresponding to amathaspiramide C was observed under
these conditions. Finally, amathaspiramide F (6) was obtained
upon treatment of 21 with lithium tetrahydroborate in THF.[17]
The spectra of our synthetic material (NMR, IR, MS) closely
match the ones published for the natural product,[1] and the
optical rotation of our sample ([a]2D5 ¼ ꢀ41.0, c ¼ 0.50, MeOH;
ref. [1]: [a]D ¼ ꢀ10, c ¼ 0.0023, MeOH) confirmed the abso-
lute configuration of our synthetic amathaspiramide F.[18]
In summary, a highly stereocontrolled total synthesis of
(ꢀ)-amathaspiramide F was achieved in six steps starting
Scheme 4. Reagents and conditions: a) 1. LDA, THF, ꢀ788C; 2. 10,
ꢀ788C!ꢀ308C, 18%. LDA ¼ lithium diisopropylamide.
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Angew. Chem. Int. Ed. 2002, 41, N o. 23

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from the known acetal 11. The synthesis features a remarkable
exception to the well-established cis rule governing SRS
chemistry, reaffirming that subtle changes in the substrate can
lead to dramatically different stereochemical outcomes. It
also presents an efficient method for circumventing a
problematic Nef reaction in the presence of densely spaced
polar functionality. Studies toward the synthesis of other
members of the amathaspiramide family, particularly ama-
thaspiramides C and E, are underway and will be reported in
due course.
[8] J. A. Tucker, T. L. Clayton, D. M. Mordas, J. Org. Chem. 1997, 62,
4370 4375.
[9] The stereochemistry of 13a and 13b was further substantiated by
NOE©s observed between the acetalic proton and benzylic protons in
both isomers.
[10] All X-ray measurements were made on a SMART CCD area detector
with graphite monochromated MoKa radiation (l ¼ 0.71069 ä). 13a
(C20H27Br2N3O4): crystal dimensions 0.32 î 0.21 î 0.13 mm, monoclin-
ic, space group P21, a ¼ 14.5715(4), b ¼ 7.7135(1), c ¼ 20.3642(5) ä,
b ¼ 108.981(1)o, V¼ 2164.43(9) ä3, Z ¼ 4, 1calcd ¼ 1.633 gcmꢀ3, 2qmax
¼
Experimental Section
49.4o, T¼ 138 K, 9660 measured reflections, 4007 independent reflec-
tions (Rint ¼ 0.061), data were corrected for Lorentz and polarization
effects, m ¼ 37.88 cmꢀ1, [d/s]max ¼ 0.00, 522 parameters refined, R ¼
0.037 (for 4982 reflections with I > 3.00s(I)), Rw ¼ 0.043, max./min.
To amide 11 (235 mg, 1.19 mmol) in THF (4.0 mL) at ꢀ788C a solution of
tBuLi in pentane (0.88 mL, 1.5m, 1.3 mmol) was added dropwise using a
syringe. After 10 min HMPA (250 mL, 1.44 mmol) was added by syringe,
and after additional 10 min the solution was allowed to warm to room
temperature over 1 h. The solution was then cooled to 08C, and TBSCl
(218 mg, 1.44 mmol) in THF (1.0 mL) was added dropwise using a cannula.
After 1 h at 08C the solution was cooled to ꢀ788C, and nitroalkene 10
(485 mg, 1.44 mmol) in THF (7.0 mL) was added dropwise by cannula.
Immediately, MgBr2¥OEt2 (372 mg, 1.44 mmol) was added in one portion.
The reaction mixture was maintained at ꢀ788C for 2 h then allowed to
warm to room temperature over 10 h. The solution was poured into
saturated NaHCO3 solution (200 mL) and extracted five times with CH2Cl2
(100 mL). The combined organic layers were washed once with brine
(100 mL), dried, filtered, and concentrated. The product was purified by
column chromatography (40% EtOAc in hexanes) to afford 459 mg (72%)
of 13a/b as a white solid. The major diastereomer 13a could be purified by
recrystallization from CH2Cl2/hexanes. The crystals obtained had a clear,
columnar appearance distinct from the yellow, blocky appearance of the
minor diastereomer 13b.
residual peaks in the final difference map 0.35/ꢀ0.53 eäꢀ3
.
17(C19H24Br2N2O5)¥0.5CH2Cl2: crystal dimensions 0.22 î 0.20 î
0.07 mm, orthorhombic, space group P212121, a ¼ 9.1876(8), b ¼
16.632(2),
c ¼ 30.276(3) ä,
V¼ 4626.3(7) ä3, Z ¼ 8,
1calcd
¼
1.619 gcmꢀ3, 2qmax ¼ 46.5o, T¼ 138 K, 18751 measured reflections,
3963 independent reflections (Rint ¼ 0.108), data were corrected for
Lorentz and polarization effects, m ¼ 36.62 cmꢀ1
,
[d/s]max ¼ 0.01,
532 parameters refined, R ¼ 0.040 (for 4202 reflections with I >
3.00s(I)), Rw ¼ 0.044, max./min. residual peaks in the final difference
map 0.32/ꢀ0.43 eäꢀ3. CCDC-188930 (13a) and CCDC-192396 (17)
contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the Cambridge Crystallographic Data Centre,
12, Union Road, Cambridge CB21EZ, UK; fax: (þ 44)1223-336-033;
or deposit@ccdc.cam.ac.uk).
[11] H. W. Pinnick in Organic Reactions, Vol. 38 (Eds.: P. Beak, R.
Bittman, E. Ciganek, S. Hanessian, L. Hegedus, R. C. Kelly, S. V.
Ley, L. E. Overman, H. J. Reich, C. J. Sih, A. B. Smith III, M.
Uskokovic), Wiley, New York, 1990, p. 655, and references therein.
[12] Nevertheless, some remarkable reactivity was noticed. For instance,
when nitro compound 18 was deprotonated to form the corresponding
nitronate and then treated with TiCl3, an unexpected cyclization
occurred that (to our knowledge) represents a conceptually novel
method for synthesizing hydrazones:
13a: [a]2D5 ¼ ꢀ21.7 (c ¼ 1.00, CHCl3); mp: 198 2008C; IR (KBr): n˜ ¼ 2966,
1694, 1549, 1476, 1368, 1251, 1058 cmꢀ1; 1H NMR (500 MHz, CDCl3, 258C):
d ¼ 7.73 (s, 1H), 6.78 (s, 1H), 4.97 (dd, J ¼ 13.5, 5.5 Hz, 1H), 4.82 (dd, J ¼
13.5, 9.5 Hz, 1H), 4.53 (dd, J ¼ 9.5, 5.5 Hz, 1H), 3.88 (s, 3H), 3.78 (s, 1H),
3.07 (m, 1H), 2.88 (s, 3H), 2.78 (m, 1H), 2.01 2.11 (m, 2H), 1.67 1.82 (m,
2H), 1.12 ppm (s, 9H); 13C NMR (125 MHz, CDCl3, 258C): d ¼ 177.5, 155.6,
136.9, 135.8, 117.7, 112.4, 111.0, 83.6, 76.7, 75.4, 56.7, 49.5, 44.6, 33.4, 30.8,
30.6,
25.3 ppm;
HRMS
(FABþ):
m/z(MꢀHþ):
calcd
for
C20H2879Br81BrN3O4: 534.0426; found: 534.0417.
Received: July 22, 2002 [Z19801]
[1] B. D. Morris, M. R. Prinsep, J. Nat. Prod. 1999, 62, 688 693.
[2] A series of related but distinct brominated alkaloids, amathamides A
G, were isolated from a Tasmanian collection of A. wilsoni Kirkpa-
trick. See a) A. J. Blackman, D. J. Matthews, Heterocycles 1985, 23,
2829 2833; b) A. J. Blackman, R. D. Green, Aust. J. Chem. 1987, 40,
1655 1662; c) A. J. Blackman, T. P. D. Eldershaw, S. M. Garland,
Aust. J. Chem. 1993, 46, 401 405.
[3] a) D. Seebach, M. Boes, R. Naef, W. B. Schweizer, J. Am. Chem. Soc.
1983, 105, 5390 5398; b) for an extensive review, see: D. Seebach,
A. R. Sting, M. Hoffmann, Angew. Chem. 1996, 108, 2880 2921;
Angew. Chem. Int. Ed. Engl. 1996, 35, 2708 2748.
[13] For recent applications of the TFA protecting group, see: a) K. C.
Nicolaou, B. S. Safina, C. Funke, M. Zak, F. J. Zÿcri, Angew. Chem.
2002, 114, 2017 2020; Angew. Chem. Int. Ed. 2002, 41, 1937 1940;
b) M. W. Carson, G. Kim, M. F. Henteman, D. Trauner, S. J. Dan-
ishefsky, Angew. Chem. 2001, 113, 4582 4584; Angew. Chem. Int. Ed.
2001, 40, 4450 4452; c) M. W. Carson, G. Kim, S. J. Danishefsky,
Angew. Chem. 2001, 113, 4585 4588; Angew. Chem. Int. Ed. 2001, 40,
4453 4456.
[4] For the use of proline-derived acetals in natural product synthesis, see:
a) R. M. Williams, T. Glinka, E. Kwast, J. Am. Chem. Soc. 1988, 110,
5927 5929; b) N. Isono, M. Mori, J. Org. Chem. 1995, 60, 115 119.
[5] For an extensive review of asymmetric Michael additions to nitro-
alkenes, see: O. M. Berner, L. Tedeschi, D. Enders, Eur. J. Org. Chem.
2002, 1877 1894.
[6] W. O. Moss, A. C. Jones, R. Wisedale, M. F. Mahon, K. C. Molloy,
R. H. Bradbury, N. J. Hales, T. Gallagher,J. Chem. Soc. Perkin Trans. 1
1992, 20, 2615 2624.
[14] M. Bartra, P. Romea, F. Urpi, J. Vilarrasa, Tetrahedron 1990, 46, 587
594.
[15] D. S. Bose, P. Srinivas, Synlett 1998, 977 978.
[16] All attempts to perform a one-pot Nef reaction on 19 to afford 21
directly were unsuccessful.
[17] Deprotection with sodium tetrahydroborate in ethanol resulted in
significant reduction of the hemiaminal function.
[18] The large discrepancy in value of the optical rotation is perhaps due to
the low concentration of the natural sample.
[7] The nitro olefin was obtained from a Henry reaction involving the
known aldehyde (H. H. Hodgson, H. G. Beard, J. Chem. Soc. 1925,
875 881) and nitromethane:
Angew. Chem. Int. Ed. 2002, 41, No. 23
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