Total syntheses of (-)-herbertenediol, (-)-mastigophorene A, and (-)- mastigophorene B. Combined utility of chiral bicyclic lactams and chiral aryl oxazolines

Article abstract of DOI:10.1021/ja984182x

A nonracemic bicyclic lactam has been used to construct a chiral cyclopentane containing vicinal quaternary carbon centers in optically pure form, which is common to all of the title compounds. An oxazoline-mediated asymmetric Ullmann coupling was then utilized to establish chirality about the biaryl axis of mastigophorenes A and B. Through the course of this synthesis, it was clearly demonstrated that smaller chiral auxiliaries lead to higher levels of atroposelection, a previously unknown phenomenon of the asymmetric Ullmann coupling.

Full text of DOI:10.1021/ja984182x

2762
J. Am. Chem. Soc. 1999, 121, 2762-2769
Total Syntheses of (-)-Herbertenediol, (-)-Mastigophorene A, and
(-)-Mastigophorene B. Combined Utility of Chiral Bicyclic Lactams
and Chiral Aryl Oxazolines
Andrew P. Degnan and A. I. Meyers*
Contribution from the Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
ReceiVed December 4, 1998
Abstract: A nonracemic bicyclic lactam has been used to construct a chiral cyclopentane containing vicinal
quaternary carbon centers in optically pure form, which is common to all of the title compounds. An oxazoline-
mediated asymmetric Ullmann coupling was then utilized to establish chirality about the biaryl axis of
mastigophorenes A and B. Through the course of this synthesis, it was clearly demonstrated that smaller
chiral auxiliaries lead to higher levels of atroposelection, a previously unknown phenomenon of the asymmetric
Ullmann coupling.
(-)-Herbertenediol (1)1,2 was isolated from the liverwort
Herberta adunca and was found to possess potent anti-lipid
peroxidation activity.3 Mastigophorenes A (2) and B (3) were
later isolated from the liverwort Mastigophora diclados and
were shown to stimulate nerve growth.4,5 It has been proposed
that both are biosynthesized via an oxidative phenolic coupling
of 1 that coexists in these liverwort extracts. Mastigophorenes
A and B were targeted for synthesis as they presented the unique
opportunity to extend the bicyclic lactam methodology6 to the
construction of a chiral cyclopentane containing vicinal qua-
ternary carbon centers, as well as to further the understanding
of the oxazoline-mediated asymmetric Ullmann coupling7,8,9
developed in this laboratory.
toward mastigophorenes A or B were carried out with simpler
analogues by Bringmann et al.10,11 In their studies, analogues
of 2 and 3 were prepared wherein the chiral cyclopentane units
were replaced by tert-butyl groups, thus omitting the more
difficult chiral centers. Herein, we describe the total synthesis
of (-)-herbertenediol (1), (-)-mastigophorene A (2), and (-)-
mastigophorene B (3), using a bicyclic lactam to construct the
chiral cyclopentane and an oxazoline-mediated asymmetric
Ullmann coupling to establish chirality about the biaryl axis of
2 and 3.
Our original focus was the synthesis of mastigophorene A
(Scheme 1), which we envisioned as arising from the reductive
removal of bisoxazoline 4. This, in turn, would be created via
an oxazoline-mediated asymmetric Ullmann coupling of mon-
omeric arylbromide 5. The latter could be elaborated from
simplified arene 6 by means of standard chemical manipulations.
The cyclopentane unit of 6 would be derived from chiral
cyclopentenone 7 via dialkylation and subsequent reduction. The
cyclopentenone would arise from chiral, nonracemic bicyclic
lactam 8, which would be prepared via diastereoselective
alkylation of the bicyclic lactam derived from ketoacid 9. It
was anticipated that ketoacid 9 could be elaborated from
commercially available phenol 10.12
Fukuyama3a has prepared herbertenediol (1) as its racemate
and intercepted one of the intermediates in his synthesis of (()-1
in an enantioselective fashion, completing a formal synthesis
of optically enriched (-)-1. To date, the only synthetic efforts
(1) (a) Matsuo, A.; Yuki, S.; Nakayama, M. Chem. Lett. 1983, 1041.
(b) Matsuo, A.; Yuki, S.; Nakayama, M. J. Chem. Soc., Perkin Trans. 1
1986, 701.
(2) The absolute configuration of 1 was firmly established by correlation
to (-)-camphonanic acid.1b
(3) (a) Fukuyama, Y.; Kiriyama, Y.; Kodama, M. Tetrahedron Lett. 1996,
37, 1261. (b) Harrowven, D. C.; Hannam, J. C. Tetrahedron Lett. 1998,
39, 9573. (c) Eicher, T.; Servet, F.; Speicher, A. Synthesis 1996, 863.
(4) Fukuyama, Y.; Asakawa, Y. J. Chem. Soc., Perkin Trans. 1 1991,
2737.
(5) The absolute configurations of 2 and 3 were assigned on the basis of
the CD exciton chirality rule.4 These syntheses further support this
stereochemical assignment.
(6) For reviews on the use of chiral bicyclic lactams in synthesis, see:
(a) Romo, D.; Meyers, A. I. Tetrahedron 1991, 47, 9503. (b) Brengel, G.
P.; Meyers, A. I. J. Chem. Soc., Chem. Comm. 1997, 1.
(7) For applications of the asymmetric oxazoline-mediated Ullmann
coupling, see: (a) Meyers, A. I.; Willemsen, J. J. Tetrahedron 1998, 54,
10493. (b) Meyers, A. I.; Willemsen, J. J. J. Chem. Soc., Chem. Commun.
1997, 1573. (c) Meyers, A. I.; Price, A. J. Org. Chem. 1998, 63, 412. (d)
Meyers, A. I.; McKennon, M. J. Tetrahedron Lett. 1995, 36, 5869. (e)
Nelson, T. D.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 3259. (f) Nelson,
T. D.; Meyers, A. I. J. Org. Chem. 1994, 59, 2655. (g) Nelson, T. D.;
Meyers, A. I. Tetrahedron Lett. 1993, 34, 3061.
(8) For a review of the use of chiral oxazolines in synthesis, see: Meyers,
A. I. J. Heterocycl. Chem. 1998, 35, 991 and references therein.
(9) For general reviews on the Ullmann reaction, see: (a) Fanta, P. E.
Synthesis 1974, 9. (b) Fanta, P. E. Chem. ReV. 1964, 64, 613. (c) Fanta, P.
E. Chem. ReV. 1946, 38, 139.
To begin (Scheme 2), phenol 10 was subjected to Mannich
conditions13 to afford benzylamine 11 in quantitative yield. It
(10) (a) Bringmann, G.; Pabst, T.; Busemann, S.; Peters, K.; Peters, E.-
M. Tetrahedron 1998, 54, 1425. (b) Bringmann, G.; Pabst, T.; Rycroft, D.
S.; Connolly, J. D. Tetrahedron Lett. 1999, 40, 483.
(11) After this paper had been accepted for publication, a synthesis of 2
and 3 was published, commencing with naturally occurring 1. Mastigo-
phorenes A and B were prepared by an oxidative dehydrodimerization of
phenolic precursors in poor yields and with little selectivity.10b
(12) Aldrich Chemicals, 1998-1999.
(13) (a) Blicke, F. F. Org. React. 1942, 1, 303. (b) Bruson, H. A.;
Macmullen, C. W. J. Am. Chem. Soc. 1941, 63, 270. (c) Mannich, C.; Ritsert,
K. Arch. Pharm. (Weinheim, Ger.) 1926, 264, 164. (d) Mannich, C.; Ball,
G. Arch. Pharm. (Weinheim, Ger.) 1926, 264, 65.
10.1021/ja984182x CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/11/1999

Syntheses of Mastigophorenes A and B
J. Am. Chem. Soc., Vol. 121, No. 12, 1999 2763
Scheme 1
Scheme 2
Scheme 3
Scheme 4
was hoped that quaternization of the benzylic amine could be
performed in tandem with methylation of the phenol. However,
all attempts to realize this outcome, including formation of the
sodium alkoxide prior to addition of methyl iodide, failed to
alkylate the phenol. Therefore, the reactions were performed in
a stepwise manner, first forming the quaternary ammonium salt
and displacing it with potassium cyanide to afford substituted
phenylacetonitrile 12 in 90% yield. Protection of the phenol as
its methyl ether under phase transfer conditions14 then proceeded
in quantitative yield. Basic hydrolysis of the nitrile gave
phenylacetic acid 13 in 97% yield. The dianion of 13 was
quenched with propylene oxide to give the γ-hydroxyacid as a
3:2 mixture of diastereomers, which was oxidized directly to
afford the requisite racemic ketoacid 9 (80% over two steps).
Condensation of 9 with (S)-valinol gave bicyclic lactam 14 as
a 3:2 mixture of epimers. However, this mixture was inconse-
quential as deprotonation of either epimer gives rise to the same
enolate. Alkylation of the latter with methyl iodide gave a 33:1
mixture of endo-exo diastereomers.15 Recrystallization from
heptane afforded the endo-alkylated product 8 as a single
diastereomer. This process has been termed a “deracemizing
alkylation” because all of the racemic ketoacid is completely
utilized in the synthesis.16
results in this laboratory suggest that this buffer system is widely
applicable to other [5.5.0] and [5.6.0] bicyclic lactams,17 yielding
the corresponding keto aldehydes in yields consistent with those
observed using Bu4NH2PO4. Base-induced cyclization of keto
aldehyde 16 afforded chiral cyclopentenone 7 in 84% from
lactam 8.
Attempts to introduce the gem-dimethyl group into 7 via
formation of the lithium enolate were unsuccessful,18 presumably
as a result of steric crowding of the adjacent quaternary carbon
center. However, deprotonation with NaH in DMF followed by
treatment with MeI allowed formation of the vicinal quaternary
carbon center in a 60% yield (Scheme 4). The remainder of
material was found to be the methyl enol ether 17, arising from
C-alkylation followed by O-alkylation. This material was
conveniently recycled via acid-catalyzed hydrolysis and resub-
jection to the previous reaction conditions, thus improving the
yield to 82% over two recycles.
Attempts to reduce the olefin (Pd/C, H2) of 18 followed by
a Wolff-Kishner reduction19 were unsuccessful; this is believed
to be a result of the well-documented steric restraints of
Reduction of bicyclic lactam 8 with Red-Al (Scheme 3) gave
carbinolamine 15, which upon hydrolysis with Bu4NH2PO4 (20
equiv) afforded keto aldehyde 16. Because of the expense of
the ammonium phosphate buffer ($209/mol),12 coupled with the
need to hydrolyze sufficient quantities of carbinolamine 15 to
allow completion of the synthesis, we screened a number of
other buffer solutions in search of a more practical alternative.
It was found that similar results could be obtained via replace-
ment of Bu4NH2PO4 with KH2PO4 ($2.11/mol).12 Unpublished
(17) The following substrates have been hydrolyzed using KH2PO3,
providing results similar to those observed using Bu4NH2PO3.
(18) (a) Meyers, A. I.; Lefker, B. A. J. Org. Chem. 1986, 51, 1541. (b)
Wenkert, E.; Buckwater, B. L.; Craviero, A. A.; Sanchez, E. L.; Sathe, S.
S. J. Am. Chem. Soc. 1978, 100, 1267.
(19) (a) Todd, D. Org. React. 1948, 4, 378. (b) Wolff, L. Liebigs Ann.
Chem. 1912, 394, 86. (c) Kishner, N. J. Russ. Phys. Chem. Soc. 1911,
43, 582.
(14) McKillop, A.; Fiaud, J.-C.; Hug, R. P. Tetrahedron 1974, 30, 1379.
1
(15) The ratio of isomers was assigned by H NMR integration.
(16) Pfau, M.; Revial, G.; Guingant, A.; d’Angelo, J. J. Am. Chem. Soc.
1985, 107, 273.

2764 J. Am. Chem. Soc., Vol. 121, No. 12, 1999
Degnan and Meyers
Scheme 5
Figure 1. Equilibration of atropisomers.
hydrazone formation.20 Furthermore, attempts to make the
sterically demanding ethylene dithioketal were also fruitless. It
was thought that we might bypass this obstacle by replacement
of oxygen with a group smaller in size than the hydrazones
and dithioketals mentioned above. Therefore, the oxygen was
replaced with sulfur, using Belleau’s reagent.21 In view of the
instability of thioenones,22 19 was utilized immediately in the
next step. Reduction with Raney Ni and H2 allowed removal
of sulfur and hydrogenation of the olefin to afford dimethyl-
herbertenediol (6) in 58% yield over two steps. Finally, removal
of the methyl groups with BBr3 provided (-)-herbertenediol in
91% yield. The synthetic product agreed in all respects with
the natural material and exhibited a rotation of -54 (c 1.0,
CHCl3), whereas the reported1 rotation for natural herbertenediol
is -47 (c 1.4, CHCl3). The structure and optical purity is further
established through the subsequent synthesis of mastigophorenes
A and B (vide supra).
Figure 2.
Scheme 6
It was now necessary to effect the dimerization of 6 and the
establishment of stereochemistry about the newly formed biaryl
axis (Scheme 5). Arene 6 was brominated (100%), followed
by oxidation23 to substituted benzoic acid 20 (84%), utilizing
conditions similar to those used by Bringmann.10a The acid was
subsequently transformed into the (S)-tert-leucinol derived
oxazoline, 5, in 82% yield under previously described condi-
tions.24
The appropriate aromatic precursor was now in hand for the
key asymmetric Ullmann coupling. Consistent with previous
studies,7e the early stages of coupling proceeded with little
atroposelectivity. However, heating the reaction mixture at reflux
was accompanied by conversion of 4 to 21 until finally a steady
state containing an equilibrium mixture of 3:1 (Figure 1) was
reached.15,25
This reaction profile can only be rationalized as a thermo-
dynamic distribution of products. One can draw two diastere-
omeric complexes wherein both of the nitrogens are chelating
to copper, each leading to a different atropisomer. The selectivity
observed corresponds to the relative stability of initially formed
copper complexes 22 and 23 (Figure 2.) In complex 22, the
tert-butyl groups are facing inward, toward one another and the
coordinated copper ion. In 23, the alkyl groups are situated on
opposite faces of the molecule, decreasing their steric interaction.
Heating the mixture at reflux allows the interconversion of 22
and 23 until an equilibrium is reached.
Although 4 and 21 are diastereomers, all attempts to separate
them were unsuccessful. However, the propensity for only one
of the bisoxazolines to coordinate to copper again became
advantageous. If the crude Ullmann coupling was not washed
with NH4OH (to remove coordinated Cu) column chromatog-
raphy gave 21 (uncomplexed) and 4 as its copper complex,
which could then be washed with NH4OH to release the
diastereomerically pure bisoxazoline 4.
(20) (a) Barton, D. H. R.; Ives, D. A. J.; Thomas, B. R. J. Chem. Soc.
1955, 2056. (b) Barton, D. H. R.; Ives, D. A. J.; Thomas, B. R. J. Chem.
Soc. 1954, 903. (c) Huang-Minlon. J. Am. Chem. Soc. 1949, 71, 3301.
(21) Lajoie, G.; Le´pine, F.; Maziak, L.; Belleau, B. Tetrahedron Lett.
1983, 24, 3815.
(22) (a) Scheibye, S.; Shabana, R.; Lawesson, S.-O.; Romming, C.
Tetrahedron 1982, 38, 993. (b) Karakasa, T.; Motoki, S. J. Org. Chem.
1978, 63, 4147 and references therein.
(23) Onopchenko, A.; Schulz, J. G. D.; Seekircher, R. J. Org. Chem.
1972, 37, 1414.
(24) Frump, J. A. Chem. ReV. 1971, 71, 483.
(25) The stereochemistry about the biaryl axis was assigned by com-
parison to previous studies of the oxazoline-mediated asymmetric Ullmann
coupling.7 It was not until completion of the syntheses of 2 and 3 that the
assignment was verified.
It was now necessary to remove the chiral oxazoline moieties.
Acidic hydrolysis to their aminoesters, protection as the bisac-
etamide (94% over two steps), and LiAlH4 reduction (90%)
afforded diol 24 (Scheme 6). Conversion to the bromide,
followed by displacement with LiAlH4, furnished tetramethyl-
mastigophorene A in 88% over two steps. Treatment with BBr3
allowed clean removal of all methyl groups, providing (-)-

Syntheses of Mastigophorenes A and B
J. Am. Chem. Soc., Vol. 121, No. 12, 1999 2765
Table 1
Scheme 7
compound
R
A-value
ratio of A:B15
5
28
29
30
31
tert-butyl
phenyl
isopropyl
ethyl
methyl
>4.5 (ref 26a)
2.9 (ref 26b)
2.1 (ref 26c)
1.8 (ref 26c)
1.8 (ref 26c)
3:1
4:1
6.4:1
7.1:1
7.2:1
mastigophorene A (2), consistent in all respects to the natural
product (observed rotation ) -68 (c 0.4, CHCl3); literature4
value ) -65 (c 0.4, CHCl3)).
Scheme 8
Although mastigophorene B could have been prepared from
the minor atropisomer produced above (21), it was deemed
favorable to construct it from an Ullmann coupling wherein (S)-
tert-leucinol has been replaced by another chiral auxiliary. As
(R)-tert-leucinol is expensive, (R)-valinol was chosen despite
the fear that this may be accompanied by even lower levels of
diastereoselection in the Ullmann coupling. Construction of
oxazoline 25 under the same conditions afforded the monomer,
ready for coupling (Scheme 7). In this case, the Ullmann reaction
gave a 6.7:1 ratio of atropisomers15sgreater than double the
selectivity seen in the tert-leucinol derived coupling! These were
also separable, with 26 isolated as its copper complex. Subjec-
tion of 26 to the sequence described above gave epimeric
mastigophorene B (3), identical to the natural product in all
respects (observed rotation ) -38 (c 0.35, CHCl3); literature4
value ) -39 (c 0.35, CHCl3)).
The observation that (R)-valinol gave higher diastereoselec-
tion than its larger (S)-tert-leucinol counterpart suggested the
possibility that the chirality of the cyclopentane rings predis-
posed the biaryl axis to the (aR) configuration. This, however,
was believed to be unlikely because of distance of the cyclo-
pentanes from the biaryl axis. Alternately, it may be possible
that tert-leucinol is simply too large to give good diastereose-
lectivity. Referring again to Figure 2, it may be that as the chiral
auxiliary gets very large, its interaction with the arene becomes
significant, favoring the “disfavored” atropisomer (22).
To identify the cause of this anomaly, a number of other chiral
auxiliaries were screened (Table 1). It was found that as the
size of the chiral auxiliary decreased (A values) the atropose-
lectivity increased, reaching a maximum of 7.2:1 for the (S)-
alaninol derived oxazoline (31). This suggests that even very
small alkyl groups in the 4-position of the oxazoline prevent
the formation of complex 22, and that the leVel of diastereo-
selection is primarily dependent on minimization of the inter-
action of the alkyl substituent with the arene in 23.
studies, a more practical method of carbinolamine hydrolysis
was developed (KH2PO4 vs Bu4NH2PO4), reducing the cost to
∼1% of the previously employed conditions. An oxazoline-
mediated asymmetric Ullmann coupling was then utilized to
generate chirality about the biaryl axis of 2 and 3. An attractive
feature of this sequence is the inclusion of the chiral auxiliary
into the oxazoline just prior to the key Ullmann coupling. The
benefits bestowed by this aspect of the synthesis are twofold.
First, advanced intermediate 20 could be coupled to favor either
2 or 3. Second, it allowed the screening of multiple chiral
auxiliaries and the realization that smaller directing groups give
higher levels of atroposelection.
Experimental Section
Thin-layer chromatography (TLC) and flash chromatography were
performed with E. Merck silica gel (230-400 mesh). All reagents were
purchased from Aldrich. All nonaqueous reactions were conducted
under an argon atmosphere in oven- or flame-dried apparatus. Mi-
croanalyses were performed by Atlantic Microlab, Inc., Norcross,
Georgia.
N,N-Dimethyl-2-hydroxy-3-methoxy-5-methylbenzylamine, 11.
To a cooled (0 °C) flask charged with 10 (94 g, 725 mmol) was added
dimethylamine (40% in H2O, 102 g, 966 mmol) with stirring.
Formaldehyde (37% in H2O, 64.5 g, 850 mmol) was slowly added,
with the temperature maintained below 40 °C. After the addition was
complete, the ice bath was removed and the mixture was allowed to
stir for 1.5 h. The mixture was poured into water (500 mL) and made
slightly acidic with 1 N HCl. The aqueous phase was extracted with
CH2Cl2 (3×), dried over Na2SO4, and concentrated to give 133 g (100%)
of a light oil: 1H NMR (300 MHz, CDCl3) δ 2.22 (s, 3H), 2.29 (s,
6H), 3.57 (s, 2H), 3.83 (s, 3H), 6.36 (d, J ) 1.5, 1H), 6.59 (d, J ) 1.5,
1H); 13C NMR (75 MHz, CDCl3) δ 20.5, 44.0, 55.4, 62.2, 111.6, 120.3,
121.3, 127.3, 144.4, 147.1.
Subjection of 32 to the conditions developed above afforded
diol 24 (Scheme 8), identical in all respects to that synthesized
previously, formally improving the synthesis of mastigophorene
A.
In summary, (-)-herbertenediol, (-)-mastigophorene A, and
(-)-mastigophorene B have been synthesized in optically pure
form. A nonracemic bicyclic lactam was used to construct a
chiral cyclopentane containing vicinal quaternary carbon centers,
which is common to all of the title compounds. During these
2-Hydroxy-3-methoxy-5-methylphenylacetonitrile, 12. To a stirred
solution of 11 (0.20 g, 1 mmol) in DMF (2 mL, 0 °C) was added MeI

2766 J. Am. Chem. Soc., Vol. 121, No. 12, 1999
Degnan and Meyers
(140 µL, 2 mmol) in one portion. The mixture was stirred for 5 min at
0 °C and 30 min at room temperature and then recooled to 0 °C. To
the crude methiodide was added freshly ground KCN (0.33 g, 5 mmol).
The mixture was stirred at 0 °C for 10 min and then at room temperature
for 1 h. The solution was poured into water (10 mL) and extracted
into ether (2×). The aqueous phase was acidified and extracted with
ether (2×). The organics were combined, washed with brine, dried over
Na2SO4, and concentrated. Flash chromatography gave 0.16 g (90%)
were washed with brine, dried over Na2SO4, and concentrated to give
15.3 g (80%) of the ketoacid as a very viscous oil: 1H NMR (300
MHz, CDCl3) δ 2.01 (s, 3H), 2.15 (s, 3H), 2.44 (dd, J ) 18.0, 3.9,
1H), 3.18 (dd, J ) 18.0, 9.9, 1H), 3.69 (s, 3H), 3.70 (s, 3H), 4.32 (dd,
J ) 9.9, 3.9, 1H), 6.46 (d, J ) 1.5, 1H), 6.52 (d, J ) 1.5, 1H), 10.5
(bs, 1H); 13C NMR (75 MHz, CDCl3) δ 21.4, 30.0, 40.3, 45.9, 55.7,
60.7, 112.8, 120.6, 131.4, 134.1, 144.3, 152.5, 179.2, 206.5; IR (thin
film) 3150(br), 1713 cm-1; HRMS (FAB+) for C14H18O5 (M)+ calcd
266.1154, found 266.1154.
1
as a white solid: mp 45.0-46.9 °C; H NMR (300 MHz, CDCl3) δ
2.28 (s, 3H), 3.67 (s, 2H), 3.86 (s, 3H), 5.61 (s, 1H), 6.63 (d, J ) 1.5,
1H), 6.74 (d, J ) 1.5, 1H); 13C NMR (75 MHz, CDCl3) δ 18.0, 21.2,
56.2, 111.6, 115.7, 118.2, 121.3, 129.8, 141.1, 146.3; IR (thin film)
3428(br), 2251 cm-1. Anal. Calcd for C10H11NO2: C 67.78, H 6.26.
Found: C 67.70, H 6.30.
exo-endo-(2,3-Dimethoxy-5-methylphenyl)bicyclic Lactam, 14. A
stirred solution of ketoacid 9 (15.3 g, 57 mmol) and (S)-valinol (6.2 g,
60 mmol) in benzene (250 mL) was heated under azeotropic removal
of water with a Dean-Stark trap for 16 h. The solution was cooled
and concentrated; the residue was taken up in ether; washed with
saturated NH4Cl, saturated Na2CO3, and brine; and then dried over
MgSO4. The solution was concentrated and filtered through a large
pad of silica gel using 40% EtOAc/Hex to yield 15.9 g (84%) of a
viscous oil, which was a 3:2 mixture of exo-endo epimers. The epimers
could be separated by careful chromatography of the mixture. Major:
[R]25D +3.56 (c 2.5, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 0.87 (d,
J ) 6.6, 3H), 1.11 (d, J ) 6.6, 3H), 1.44 (s, 3H), 1.70 (m, 1H), 2.09
(dd, J ) 14.4, 6.3, 1H), 2.24 (s, 3H), 2.66 (dd, J ) 13.8, 10.8, 1H),
3.68 (m, 1H), 3.76 (s, 3H), 3.78 (m, 1H), 3.80 (s, 3H), 3.89 (dd, J )
11.1, 6.3, 1H), 4.18 (t, J ) 8.1, 1H), 6.50 (d, J ) 1.5, 1H), 6.61 (d, J
) 1.5, 1H); 13C NMR (75 MHz, CDCl3) δ 14.6, 16.5, 16.9, 20.4, 29.6,
36.0, 41.4, 51.1, 55.9, 59.0, 65.8, 94.5, 108.0, 116.8, 129.0, 129.2, 140.0,
147.9, 177.6; IR (thin film) 1712 cm-1; HRMS (EI+) for C19H27NO4
(M)+ calcd 333.1940, found 333.1935.
2,3-Dimethoxy-5-methylphenylacetic Acid, 13. A 1 L flask was
charged with 12 (49.5 g, 283 mmol), LiOH‚H2O (17.8 g, 424 mmol),
and benzyltributylammonium chloride (17.6 g, 56 mmol). To this was
added water (400 mL), and the solution was allowed to stir for 1 min.
CH2Cl2 (400 mL) was added, and the heterogeneous mixture was stirred
for 1 min. To this was added Me2SO4 (40 mL, 424 mmol), and the
mixture was vigorously stirred for 5 min. The layers were separated,
and the aqueous layer was washed with CH2Cl2 (2×). The organics
were washed with brine, dried over Na2SO4, and concentrated. The oil
was taken up in EtOAc and filtered through a large pad of silica gel,
eluting with EtOAc to yield 54 g (100%) of 2,3-dimethoxy-5-
methylphenylacetonitrile as a light oil: 1H NMR (300 MHz, CDCl3) δ
2.29 (s, 3H), 3.66 (s, 2H), 3.83 (s, 3H), 3.84, (s, 3H), 6.69 (s, 1H),
6.74 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 18.2, 21.0, 55.5, 60.4,
113.2, 118.2, 121.0, 123.4, 134.1, 144.2, 152.1; IR (thin film) 2251
Minor: [R]25D +35.9 (c 2.0, CH2Cl2); 1H NMR (300 MHz, CDCl3)
δ 0.87 (d, J ) 6.2, 3H), 1.00 (d, J ) 6.5, 3H), 1.51 (s, 3H), 1.69 (m,
1H), 2.22 (s, 3H), 2.32 (t, J ) 11.1, 1H), 2.48 (dd, J ) 12.9, 8.7, 1H),
3.69 (m, 1H), 3.76 (s, 3H), 3.78 (s, 3H), 3.89 (dd, J ) 8.7, 5.4, 1H),
4.19 (m, 2H), 6.49 (s, 1H), 6.60 (s, 1H); 13C NMR (75 MHz, CDCl3)
δ 14.7, 15.9, 16.8, 20.9, 28.5, 39.3, 41.4, 51.2, 56.2, 57.4, 66.2, 92.6,
108.1, 117.4, 127.1, 129.0, 140.6, 147.7, 173.8; IR (thin film) 1713
cm-1
.
To a stirred solution of 2,3-dimethoxy-5-methylphenylacetonitrile
(53.7 g, 281 mmol) in methanol (450 mL) was added aqueous 25%
NaOH (125 mL). The mixture was heated at reflux for 24 h; upon
cooling, the solution was concentrated, redissolved in water, and
extracted with ether (2×), and the ethereal layers were discarded. The
aqueous phase was acidified with cold concentrated HCl and extracted
into ether (3×), which was washed with brine, dried over Na2SO4, and
concentrated to give 57.1 g (97%) of the acid as a white solid: mp
cm-1
.
endo-Methyl-(2,3-Dimethoxy-5-methylphenyl)bicyclic Lactam, 8.
To a stirred solution of diisopropylamine (12.6 mL, 90 mmol) in THF
(350 mL, 0 °C) was added n-BuLi (2.62 M in hexanes, 33 mL, 86.3
mmol). The solution was stirred for 30 min and cooled to -78 °C. To
this was added 14 (23 g, 69 mmol) in THF (100 mL) via cannula, and
the mixture was allowed to stir for 1 h. The solution was cooled to
-100 °C, and MeI (11 mL, 180 mmol) was added dropwise. The
mixture was stirred for 2 h, quenched by addition of water, and
concentrated. The residue, a 33:1 ratio of alkylation epimers, was taken
up in 20% EtOAc/Hex and filtered through a large pad of silica gel to
give a white solid. This was recrystallized from n-heptane to yield 19.7
g (82%) of a white solid as a single diastereomer. The minor
diastereomer was isolated by successive recrystallizations of the mother
liquor to afford a 1:1 mixture of diastereomers. Careful chromatography
1
101-102 °C; H NMR (300 MHz, CDCl3) δ 2.29 (s, 3H), 3.64 (s,
2H), 3.81 (s, 3H), 3.83 (s, 3H), 6.63 (d, J ) 1.5, 1H), 6.67 (d, J ) 1.5,
1H), 10.43 (bs, 1H); 13C NMR (75 MHz, CDCl3) δ 21.2, 35.5, 55.6,
60.5, 112.8, 123.0, 127.1, 133.7, 145.0, 152.2, 178.2; IR (thin film)
3000(br), 1698 cm-1. Anal. Calcd for C11H14O4: C 62.85, H 6.71.
Found: C 63.05, H 6.65.
2-(2,3-Dimethoxy-5-methylphenyl)-4-oxopentanoic Acid, 9. A
stirred solution of diisopropylamine (22 mL, 156 mmol) in THF (350
mL, 0 °C) was treated with n-BuLi (2.19 M in hexanes, 68 mL, 148
mmol), stirred for 30 min, and cooled to -78 °C. To this was added
13 (15 g, 71 mmol) in THF (100 mL) via cannula. The flask was placed
in a 0 °C bath and stirred for 45 min before recooling to -78 °C.
(()-Propyleneoxide (13.7 mL, 195 mmol) was then added. The flask
was placed in a 0 °C bath and stirred overnight while allowed to reach
room temperature. The mixture was quenched with water and concen-
trated by rotary evaporation. The crude alcohol was taken up in water
and extracted with ether (2×), and the ethereal layers were discarded.
The aqueous layer was acidified with concentrated HCl and extracted
with ether (3×). These organic layers were washed with brine, dried
over Na2SO4, and concentrated to give a viscous oil. This crude
γ-hydroxyacid was taken on directly below.
To a stirred solution of oxalyl chloride (6.8 mL, 79 mmol) in CH2-
Cl2 (350 mL, -78 °C) was added DMSO (10 mL, 143 mmol), and the
mixture was allowed to stir for 15 min before addition of the crude
hydroxyacid in CH2Cl2 (100 mL). The solution was allowed to stir for
1 h. To this was added Et3N (40 mL, 288 mmol), and the mixture was
stirred for 5 min. The cold bath was removed, and the mixture was
allowed to reach room temperature. It was quenched by addition to
water (200 mL) containing NaOH (9 g, 225 mmol), and the layers
were separated. The organic layer was washed with 5% NaOH (2×);
the aqueous extracts were combined and washed with ether (2×), and
the ethereal solutions were discarded. The aqueous layer was acidified
with cold concentrated HCl and extracted into CH2Cl2 (3×). These
of the enriched material then afforded the minor diastereomer. Major
1
(8): mp 109-110 °C; [R]25 -46.7 (c 0.9, CH2Cl2); H NMR (300
D
MHz, CDCl3) δ 0.87 (d, J ) 6.6, 3H), 1.12 (d, J ) 6.6, 3H), 1.28 (s,
3H), 1.49 (s, 3H), 1.70 (m, 1H), 2.19 (d, J ) 13.5, 1H), 2.25 (s, 3H),
2.60 (d, J ) 13.5, 1H), 3.67 (m, 1H), 3.79 (s, 3H), 3.81 (s, 3H), 4.18
(dd, J ) 8.7, 7.5, 1H), 6.64 (s, 2H); 13C NMR (75 MHz, CDCl3) δ
18.8, 20.6, 21.2, 24.1, 25.4, 33.8, 48.1, 50.3, 55.2, 59.5, 63.1, 69.9,
97.3, 112.0, 119.6, 132.4, 136.6, 144.0, 152.1, 184.1; IR (thin film)
1711 cm-1. Anal. Calcd for C20H29NO4: C 69.14, H 8.41 N 4.03.
Found: C 69.08, H 8.41, N 3.99.
Minor: oil, [R]25 +64.1 (c 2.4, CH2Cl2); 1H NMR (300 MHz,
D
CDCl3) δ 0.90 (d, J ) 6.6, 3H), 1.05 (d, J ) 6.6, 3H), 1.55 (s, 3H),
1.67 (s, 3H), 1.70 (m, 1H), 2.07 (d, J ) 13.2, 1H), 2.28 (s, 3H), 2.62
(d, J ) 13.2, 1H), 3.76 (s, 3H), 3.78 (s, 3H), 3.82 (m, 1H), 4.29 (dd,
J ) 8.4, 7.8, 1H), 6.65 (s, 1H), 6.74 (s, 1H); 13C NMR (75 MHz, CDCl3)
δ 14.6, 16.1, 17.0, 20.4, 22.6, 29.6, 45.5, 46.5, 51.2, 55.2, 57.4, 66.2,
92.3, 108.6, 115.0, 127.6, 132.1, 139.8, 147.8, 178.2; IR (thin film)
1714 cm-1
.
(S)-4-(2,3-Dimethoxy-5-methylphenyl)-4-methylcyclopenten-
one, 7. To a stirred solution of 8 (10 g, 29 mmol) in THF (300 mL,
-78 °C) was added Red-Al (65+ wt %, 10 mL, 33 mmol). The mixture

Syntheses of Mastigophorenes A and B
J. Am. Chem. Soc., Vol. 121, No. 12, 1999 2767
was allowed to reach room temperature, stirred for 24 h, quenched by
addition of MeOH, and concentrated. The residue was taken up in water,
extracted with ether (2×), made strongly basic with 20% KOH, and
extracted with ether (2×). The combined extracts were washed with
brine, dried over Na2SO4, and concentrated to give the crude carbino-
lamine. This was dissolved in 95% EtOH (460 mL) and added to a
stirred solution of KH2PO4 (78.4 g, 576 mmol) in water (690 mL), and
the mixture was stirred 12 h. The suspension was concentrated,
dissolved in water, and extracted with ether (3×). The organics were
washed with brine, dried over Na2SO4, and concentrated to give the
crude keto aldehyde as a viscous oil. This was dissolved in absolute
EtOH (500 mL), treated with 1 M KOH in EtOH (1.5 mL), and heated
at reflux for 2 h. The solution was cooled, treated with silica gel, and
concentrated to adsorb the crude cyclopentenone. Column chromatog-
1H NMR (300 MHz, CDCl3) δ 0.77 (s, 3H), 1.20 (s, 3H), 1.42 (s, 3H),
1.50-1.80 (m, 5H), 2.23 (s, 3H), 2.61 (m, 1H), 5.32 (s, 1H), 5.41 (s,
1H), 6.55 (d, J ) 1.5, 1H), 6.69 (d, J ) 1.5, 1H); 13C NMR (75 MHz,
CDCl3) δ 20.5, 21.3, 23.0, 25.6, 27.0, 39.4, 41.1, 45.0, 51.3, 113.6,
122.1, 128.8, 133.7, 141.1, 143.5; IR (thin film) 3507, 2959, 1300 cm-1
.
Anal. Calcd for C15H22O2: C 76.88, H 9.46. Found: C 77.08, H 9.60.
(S)-2-Bromo-3,4-dimethoxy-5-(1,2,2-trimethylcyclopentyl)benzo-
ic Acid, 20. To a stirred solution of 6 (2.08 g, 7.95 mmol) in CH2Cl2
(42 mL, -10 °C) was added bromine (412 µL, 8.0 mmol) dropwise.
After 5 min, the solution was poured into saturated NaHCO3, extracted
into CH2Cl2 (2×), washed with brine, dried over Na2SO4, and
concentrated. Trace impurities were removed via flash chromatography
(2% EtOAc/Hex) to give 2.71 g (100%) of (S)-1,2,2-trimethyl-1-(2,3-
dimethoxy-4-bromo-5-methylphenyl)cyclopentane as a colorless oil:
raphy (20% EtOAc/Hex) gave 5.95 g (84%) as a colorless oil: [R]25
1
[R]25 -14.5 (c 1.3, CH2Cl2); H NMR (300 MHz, CDCl3) δ 0.66 (s,
D
D
1
+38.3 (c 1.5, CH2Cl2); H NMR (300 MHz, CDCl3) δ 1.53 (s, 3H),
3H), 1.09 (s, 3H), 1.31 (s, 3H), 1.71 (m, 5H), 2.32 (s, 3H), 2.52 (m,
1H), 3.78 (s, 3H), 3.79 (s, 3H), 6.95 (s, 1H); 13C NMR (75 MHz, CDCl3)
δ 20.6, 23.2, 24.2, 25.4, 27.0, 39.3, 41.1, 45.0, 51.7, 59.9, 60.5, 117.7,
125.8, 132.2, 139.9, 150.9, 152.0; HRMS (EI+) for C17H25NO2Br (M)+
calcd 340.1038, found 340.1029; HRMS (EI+) for C23H35NO381Br
(M)+ calcd 342.1017, found 342.1016.
2.27 (s, 3H), 2.57 (d, J ) 18.6, 1H), 2.69 (d, J ) 18.6, 1H), 3.73 (s,
3H), 3.81 (s, 3H), 6.12 (d, J ) 6.0, 1H), 6.54 (d, J ) 1.5, 1H), 6.64 (d,
J ) 1.5, 1H), 7.82 (d, J ) 5.4, 1H); 13C NMR (75 MHz, CDCl3) δ
21.5, 28.3, 47.3, 51.1, 55.7, 60.5, 112.5, 119.2, 130.6, 133.0, 138.0,
145.1, 153.0, 171.4, 209.8; IR (thin film) 1715 cm-1. Anal. Calcd for
C15H18O3: C 73.15, H 7.37. Found: C 72.94, H 7.39.
A pressure tube was charged with (S)-1,2,2-trimethyl-1-(2,3-
dimethoxy-4-bromo-5-methylphenyl)-cyclopentane (2.70 g, 7.9 mmol),
Co(OAc)2‚4H2O (0.66 g, 2.64 mmol), methyl ethyl ketone (2.84 mL,
32 mmol), and glacial acetic acid (25 mL). The tube was sealed,
pressurized with oxygen (10 psi), and heated to 110 °C. The pressure
was raised to 80 psi, and the mixture was allowed to stir for 4 h. The
tube was depressurized and poured onto 3 volumes of ice to give a
(S)-4,5,5-Trimethyl-4-(2,3,dimethoxy-5-methylphenyl)cyclopen-
tenone, 18. To a stirred suspension of NaH (1.78 g, 74 mmol) in DMF
(30 mL) was added a solution of cyclopentenone 7 (6.6 g, 26.9 mmol)
in DMF (20 mL) via cannula. The mixture was placed in a 10 °C bath,
and MeI (4.4 mL, 70 mmol) was added. The bath was removed, and
the mixture was stirred at room temperature. The bath was replaced as
necessary to maintain a temperature below 40 °C. After the exotherm
ceased, the bath was removed and the solution was allowed to stir
overnight. The mixture was poured into water (250 mL), extracted into
ether (4×), washed with water and brine, dried over Na2SO4, and
concentrated to give an oil. The residue was recrystallized from heptane
to give 3.96 g (54%) of 18 as a white solid. The mother liquor (17)
was concentrated and redissolved in 3:1 THF/1 N HCl. After 10 min,
the mixture was quenched by addition of NaHCO3 and concentrated.
The residue was taken up in water, extracted into ether (3×), washed
with brine, dried over Na2SO4, and concentrated. This was resubjected
to the conditions above, using 1.5 equiv NaH and 1.25 equiv MeI.
white precipitate. This was filtered to give 2.46 g (84%) of the acid as
1
crystalline solid: mp 163-165 °C; [R]25 -37.3 (c 1.1, CH2Cl2); H
D
NMR (300 MHz, CDCl3) δ 0.68 (s, 3H), 1.12 (s, 3H), 1.34 (s, 3H),
1.75 (m, 5H), 2.52 (m, 1H), 3.80 (s, 3H), 3.89 (s, 3H), 7.84 (s, 1H),
12.35 (bs, 1H); 13C NMR (75 MHz, CDCl3) δ 15.8, 19.2, 20.7, 22.3,
34.8, 36.5, 40.3, 47.2, 55.4, 56.0, 112.6, 120.1, 124.2, 136.0, 147.2,
153.3, 167.3; IR (thin film) 3150(br), 1695 cm-1. Anal. Calcd for
C17H23O4Br: C 55.00, H 6.24. Found: C 54.99, H 6.17.
(S)-tert-Leucinol-o-bromoaryloxazoline, 5. To a stirred solution
of 20 (1.0 g, 2.7 mmol) in CH2Cl2 (10 mL) was added oxalyl chloride
(0.35 mL, 4.0 mmol), followed by 1 drop of DMF. After 1 h, the
solution was concentrated, redissolved in CH2Cl2 (10 mL), and cooled
to 0 °C. To this was added a solution of (S)-tert-leucinol (0.38 g, 3.2
mmol) and Et3N (0.49 mL, 3.5 mmol) in CH2Cl2 (5 mL). The ice bath
was removed, and the mixture was stirred for 6 h. The solution was
poured into 2% NaHCO3, and the layers were separated and extracted
twice more with CH2Cl2. The organics were combined, washed with
brine, dried over MgSO4, filtered, and concentrated. The residue was
dissolved in CH2Cl2 (10 mL), treated with SOCl2 (394 µL, 5.4 mmol),
and stirred for 2 h at room temperature. The solvent was removed, and
the residue was dissolved in CH3CN (10 mL), treated with 20% K2-
CO3, and heated to reflux. After 5 h, the heterogeneous mixture was
concentrated to remove the CH3CN and extracted with ether (3×). The
extracts were washed with brine, dried over Na2SO4, and concentrated.
Flash chromatography gave 1.0 g (82%) as a viscous oil: [R]25D -79.4
Two recycles gave an additional 2.0 g (28%): mp 84.0-85.9 °C; [R]25
D
1
-79.4 (c 1.0, CH2Cl2); H NMR (300 MHz, CDCl3) δ 0.64 (s, 3H),
1.22 (s, 3H), 1.46 (s, 3H), 2.27 (s, 3H), 3.78 (s, 3H), 3.82 (s, 3H), 6.05
(d, J ) 6.0, 1H), 6.46 (s, 1H), 6.63 (d, J ) 1.5, 1H), 7.91 (d, J ) 5.7,
1H); 13C NMR (75 MHz, CDCl3) δ 19.7, 21.4, 26.1, 50.9, 54.7, 55.6,
60.3, 112.1, 120.6, 125.8, 132.8, 136.0, 145.3, 152.8, 171.4, 214.6; IR
(thin film) 1705 cm-1. Anal. Calcd for C17H22O3: C 74.42, H 8.08.
Found: C 74.30, H 8.10.
(S)-O,O′-Dimethylherbertenediol, 6. A flask was charged with
cyclopentenone 18 (1.93 g, 7.0 mmol), Belleau’s reagent (2.23 g, 4.23
mmol), and toluene (65 mL). The solution was heated to reflux and
held there for 30 min. The solution was cooled, filtered through
Fluorosil, washed with CH2Cl2, and concentrated to yield a bright pink
oil, which was subjected to flash chromatography (5% EtOAc/Hex),
taking all pink fractions. The residue was dissolved in EtOH (75 mL),
and Raney Ni was added in portions with stirring until the solution
was colorless. A hydrogen balloon was affixed, and stirring was
continued overnight. The solution was filtered to give the crude
cyclopentane. Flash chromatography (4% EtOAc/Hex) gave 1.05 g
(58%) as a colorless oil: [R]25D -27.0 (c 1.3, CH2Cl2); 1H NMR (300
MHz, CDCl3) δ 0.67 (s, 3H), 1.10 (s, 3H), 1.33 (s, 3H), 1.70 (m, 5H),
2.27 (s, 3H), 2.61 (m, 1H), 3.74 (s, 3H), 3.80 (s, 3H), 6.58 (d, J ) 1.8,
1H), 6.73 (d, J ) 1.5, 1H); 13C NMR (75 MHz, CDCl3) δ 20.5, 21.8,
24.3, 25.4, 27.0, 39.1, 41.1, 45.1, 51.7, 55.7, 60.5, 111.2, 121.8, 131.7,
140.2, 146.8, 153.2.
(-)-Herbertenediol, 1. To a stirred solution of dimethylherbertene-
diol (100 mg, 0.38 mmol) in CH2Cl2 (2 mL) at 0 °C was added BBr3
(1 M in CH2Cl2, 1.5 mL, 1.5 mmol). The ice bath was removed, and
after 40 min the solution was poured into 2% NaHCO3, extracted into
CH2Cl2 (3×), washed with brine, dried over Na2SO4, and concentrated.
Column chromatography (20% EtOAc/Hex) gave 81 mg (91%) as a
white crystalline solid: mp 89.9-90.5 °C; [R]25D -53.8 (c 1.0, CHCl3);
1
(c 1.0, CH2Cl2); H NMR (300 MHz, CDCl3) δ 0.66 (s, 3H), 0.97 (s,
9H), 1.09 (s, 3H), 1.31 (s, 3H), 1.68 (m, 5H), 2.49 (m, 1H), 3.77 (s,
3H), 3.83 (s, 3H), 4.05 (dd, J ) 10.2, 7.8, 1H), 4.21 (dd, J ) 8.1, 8.1,
1H), 4.33 (dd, J ) 10.5, 9.0, 1H), 7.38 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 20.4, 23.7, 25.4, 26.1, 27.0, 34.1, 39.4, 41.2, 44.8, 51.7, 59.9,
60.5, 68.9, 76.7, 115.7, 124.8, 126.6, 140.6, 151.4, 155.7, 163.0; IR
(thin film) 1660 cm-1; HRMS (FAB+) for C23H35NO3Br (M+H)+ calcd
452.1800, found 452.1786; HRMS (FAB+) for C23H35NO381Br
(M+H)+ calcd 454.1780, found 454.1775.
(S)-Phenylglycinol-o-bromoaryloxazoline, 28. Prepared from 20
by the same procedure as 5, using (S)-phenylglycinol in place of (S)-
tert-leucinol, in 83% yield as a colorless oil: [R]25 -35.3 (c 1.0,
D
1
CHCl3); H NMR (300 MHz, CDCl3) δ 0.70 (s, 3H), 1.13 (s, 3H),
1.35 (s, 3H), 1.45-1.85 (m, 5H), 2.54 (m, 1H), 3.81 (s, 3H), 3.88 (s,
3H), 4.24 (dd, J ) 8.4, 8.4, 1H), 4.79 (dd, J ) 10.2, 8.4, 1H), 5.42
(dd, J ) 9.9, 8.4, 1H), 7.23-7.38 (m, 5H), 7.55 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 20.6, 23.8, 25.5, 27.2, 39.5, 41.3, 45.0, 51.9, 60.1,

2768 J. Am. Chem. Soc., Vol. 121, No. 12, 1999
Degnan and Meyers
60.6, 70.7, 75.1, 116.0, 124.3, 126.9, 127.0, 127.7, 128.9, 140.9, 142.4,
(S)-Alaninol-bisoxazoline, 32. Prepared from 31 by the same
151.5, 156.1, 164.6; IR (thin film) 1651 cm-1
.
procedure as 4 in 66% yield as an amorphous solid. Major: [R]25
D
1
-87.9 (c 1.1, CHCl3); H NMR (300 MHz, CDCl3) δ 0.69 (s, 6H),
(S)-Valinol-o-bromoaryloxazoline, 29. Prepared from 20 by the
1.12 (d, 6H), 1.13 (s, 6H), 1.38 (s, 6H), 1.50-1.90 (m, 10H), 2.71 (m,
2H), 3.50 (m, 2H), 3.52 (s, 6H), 3.79 (s, 6H), 4.07 (m, 4H), 7.62 (s,
2H); 13C NMR (75 MHz, CDCl3) δ 20.6, 21.4, 24.1, 25.6, 27.3, 39.0,
41.3, 45.2, 51.8, 59.5, 60.1, 62.0, 73.9, 122.8, 125.2, 130.4, 139.7, 151.5,
same procedure as 5, using (S)-valinol in place of (S)-tert-leucinol, in
1
85% yield as a colorless oil: [R]25 -46.6 (c 1.3, CH2Cl2); H NMR
D
(300 MHz, CDCl3) δ 0.66 (s, 3H), 0.96 (d, J ) 7.0, 3H), 1.03 (d, J )
6.6, 3H), 1.10 (s, 3H), 1.32 (s, 3H), 1.40-2.00 (m, 6H), 2.48 (m, 1H),
3.78 (s, 3H), 3.84 (s, 3H), 4.13 (m, 2H), 4.39 (dd, J ) 12.9, 11.4, 1H),
7.40 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 18.2, 18.9, 20.4, 23.6,
25.4, 27.0, 32.7, 39.3, 41.2, 44.8, 51.7, 59.9, 60.4, 70.2, 72.9, 115.7,
154.9, 164.3; IR (thin film) 1651 cm-1
.
(R)-Valinol-bisoxazoline, 26. Prepared from 25 by the same
procedure as 4 in 74% yield as an amorphous solid. Major: [R]25
D
124.7, 126.6, 140.6, 151.3, 155.7, 163.0; IR (thin film) 1655 cm-1
.
+43.9 (c 1.3, CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.70 (d, J ) 6.6,
6H), 0.72 (s, 6H), 0.79 (d, J ) 6.6, 6H), 1.15 (s, 6H), 1.41 (s, 6H),
1.45-1.85 (m, 12H), 2.62 (m, 2H), 3.58 (s, 6H), 3.63 (m, 4H), 3.83
(s, 6H), 3.95 (dd, J ) 8.7, 7.2, 2H), 7.57 (s, 2H); 13C NMR (75 MHz,
CDCl3) δ 18.3, 19.1, 20.4, 23.5, 25.4, 27.1, 32.8, 39.4, 41.2, 44.7, 51.5,
59.2, 59.9, 69.6, 72.7, 122.3, 124.6, 131.0, 139.1, 151.2, 154.7, 163.4;
IR (thin film) 1652 cm-1. Anal. Calcd for C44H64N2O6: C 73.71, H
9.00, N 3.91. Found: C 73.53, H 9.01, N 3.73.
(S)-2-Aminobutanol-o-bromoaryloxazoline, 30. Prepared from 20
by the same procedure as 5, using (S)-2-aminobutanol in place of (S)-
tert-leucinol, in 77% yield as a colorless oil: [R]25 +1.86 (c 0.7,
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.66 (s, 3H), 1.00 (t, J ) 7.2,
3H), 1.10 (s, 3H), 1.31 (s, 3H), 1.40-1.85 (m, 6H), 2.48 (m, 1H), 3.77
(s, 3H), 3.84 (s, 3H), 4.05 (dd, J ) 7.8, 7.8, 1H), 4.26 (m, 1H), 4.45
(dd, J ) 8.4, 8.4, 1H), 7.39 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 9.9,
20.4, 23.7, 25.4, 27.0, 28.6, 39.3, 41.2, 44.8, 51.7, 59.9, 60.4, 68.3,
72.1, 115.7, 124.6, 126.5, 140.6, 151.3, 155.7, 163.1; IR (thin film)
Biaryldiol, 24. Bisoxazoline 4 (95 mg, 0.13 mmol) was dissolved
in THF (2 mL) and 1 N HCl (2 mL). The solution was stirred at room
temperature for 3 d. It was poured into saturated NaHCO3, extracted
into ether (3×), washed with brine, dried over Na2SO4, and concentrated
to give the crude intermediate bisaminoester. The residue was dissolved
in CH2Cl2 (5 mL) and treated with Ac2O (30 µL, 0.31 mmol), Et3N
(50 µL, 0.35 mmol), and a crystal of DMAP. After 2 h of stirring, the
solution was poured into saturated NaHCO3, extracted into CH2Cl2 (3×),
dried over Na2SO4, and concentrated. Flash chromatography (50%
EtOAc/Hex) gave 0.103 g (94%) of the (S)-tert-leucinol derived
1653 cm-1
.
(S)-Alaninol-o-bromoarylozazoline, 31. Prepared from 20 by the
same procedure as 5, using (S)-alaninol in place of (S)-tert-leucinol, in
1
98% yield as a colorless oil: [R]25 -15.1 (c 1.1, CHCl3); H NMR
D
(300 MHz, CDCl3) δ 0.62 (s, 3H), 1.07 (s, 3H), 1.29 (s, 3H), 1.32 (d,
J ) 6.3, 3H), 1.50-1.80 (m, 5H), 2.48 (m, 1H), 3.75 (s, 3H), 3.81 (s,
3H), 3.91 (dd, J ) 7.2, 7.2, 1H), 4.38 (m, 1H), 4.45 (dd, J ) 9.6, 7.8,
1H), 7.39 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 20.5, 21.6, 23.7, 25.5,
27.1, 39.4, 41.3, 44.8, 51.7, 60.0, 60.5, 62.5, 74.2, 115.8, 124.5, 126.7,
bisacetamide as an amorphous solid: [R]25 -68.5 (c 1.0, CH2Cl2);
D
140.7, 151.4, 155.8, 163.1; IR (thin film) 1651 cm-1
.
1H NMR (300 MHz, CDCl3) δ 0.66 (s, 6H), 0.82 (s, 18H), 1.10 (s,
6H), 1.40 (s, 6H), 1.45-1.85 (m, 10H), 1.87 (s, 6H), 2.58 (m, 2H),
3.33 (s, 6H), 3.80 (s, 6H), 3.94 (m, 4H), 4.27 (m, 2H), 5.75 (d, J )
9.6, 2H), 7.75 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 20.6, 23.5, 23.7,
25.5, 27.0, 27.0, 34.1, 39.4, 41.2, 45.1, 51.9, 55.8, 59.3, 60.2, 63.9,
124.6, 126.2, 131.0, 139.8, 151.0, 156.5, 167.4, 170.0; IR (thin film)
(R)-Valinol-o-bromoaryloxazoline, 25. Prepared from 20 by the
same procedure as 5, using (R)-valinol in place of (S)-tert-leucinol, in
1
85% yield as a colorless oil: [R]25 +7.53 (c 1.5, CH2Cl2); H NMR
D
(300 MHz, CDCl3) δ 0.66 (s, 3H), 0.95 (d, J ) 7.0, 3H), 1.03 (d, J )
6.9, 3H), 1.10 (s, 3H), 1.31 (s, 3H), 1.40-1.95 (m, 6H), 2.48 (m, 1H),
3.77 (s, 3H), 3.84 (s, 3H), 4.13 (m, 2H), 4.38 (dd, J ) 12.9, 11.4, 1H),
7.39 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 18.2, 18.9, 20.4, 23.7,
25.4, 27.0, 32.7, 39.3, 41.2, 44.8, 51.7, 59.9, 60.4, 70.1, 72.9, 115.7,
3305(br), 1727, 1660 cm-1
.
To a stirred suspension of LiAlH4 (46 mg, 1.2 mmol) in THF (5
mL, 0 °C) was added the (S)-tert-leucinol derived bisacetamide (200
mg, 0.23 mmol). The solution was warmed to room temperature and
stirred for 2 h. The solution was quenched by addition of MeOH,
followed by 20% aqueous KOH. The solid was filtered, and the eluent
was concentrated. Column chromatography (20% EtOAc/Hex) gave
115 mg (90%) of the diol as an amorphous solid: [R]25D +71.5 (c 1.2,
124.7, 126.5, 140.6, 151.3, 155.7, 162.9; IR (thin film) 1658 cm-1
.
(S)-tert-Leucinol-bisoxazoline, 4. A 10 mL flask with stirbar was
charged with 5 (300 mg, 0.66 mmol), freshly activated27 Cu (150 mg,
2.3 mmol), and DMF (1 mL). The mixture was heated to 95 °C for 8
h and then diluted with DMF (5 mL). A condenser was affixed, and
the mixture was heated to reflux. After 3 d, the mixture was filtered
through cotton to remove excess Cu, poured into water, and extracted
into ether (3×). The organics were washed with water (2×) and then
brine, dried over Na2SO4, and concentrated. Flash chromatography (5-
50% EtOAc/Hex) gave the biaryl as its copper complex. This was taken
up in ether, washed with NH4OH (2×) and brine, and dried over Na2-
1
CHCl3); H NMR (300 MHz, CDCl3) δ 0.68 (s, 6H), 1.14 (s, 6H),
1.43 (s, 6H), 1.45-1.75 (m, 10H), 2.60 (m, 2H), 3.09 (bs, 2H), 3.54
(s, 6H), 3.79 (s, 6H), 4.14 (d, J ) 11.7, 2H),4.20 (d, J ) 11.1, 2H),
7.26 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 20.6, 23.7, 25.6, 27.2,
39.4, 41.3, 45.2, 51.9, 60.0, 60.3, 64.4, 126.2, 127.9, 134.4, 141.2, 150.7,
152.8; IR (thin film) 3362(br) cm-1. Anal. Calcd for C34H50O6: C 73.61,
H 9.08. Found: C 73.77, H 9.19.
SO4 to yield the 0.158 g (64%) as a single atropisomer. Major (4):
1
[R]25 -50.6 (c 1.1, CH2Cl2); H NMR (300 MHz, CDCl3) δ 0.70 (s,
D
Biaryldiol, 27. The (R)-valinol derived bisacetamide was prepared
from 26, by the same procedure used to prepare the (S)-tert-leucinol
derived bisacetamide (en route to 24), in 93% yield as an amorphous
18H), 0.75 (s, 6H), 1.15 (s, 6H), 1.37 (s, 6H), 1.50-1.90 (m, 10H),
2.68 (m, 2H), 3.55 (s, 6H), 3.71 (m, 4H), 3.79 (s, 6H), 3.92 (dd, J )
9.6, 8.1, 2H), 7.76 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 20.6, 24.4,
25.3, 26.1, 27.3, 33.8, 38.9, 41.3, 45.1, 51.7, 59.6, 60.0, 68.1, 76.3,
123.0, 125.2, 131.0, 139.3, 151.3, 154.7, 163.4; IR (thin film) 1655
cm-1. Anal. Calcd for C46H68N2O6: C 74.16, H 9.20. Found: C 73.92,
solid: [R]25 +23.5 (c 1.2, CHCl3); H NMR (300 MHz, CDCl3) δ
1
D
0.76 (m, 18H), 1.10 (s, 6H), 1.25-1.90 (m, 12H), 1.35 (s, 6H), 1.88
(s, 6H), 2.69 (m, 2H), 3.41 (s, 6H), 3.75 (m, 2H), 3.78 (s, 6H), 3.95
(dd, J ) 11.7, 3.6, 2H), 4.07 (dd, J ) 11.4, 5.7, 2H), 5.78 (d, J ) 9.0,
2H), 7.82 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 19.1, 19.3, 20.4, 23.3,
24.5, 25.0, 26.9, 29.2, 38.4, 40.8, 45.3, 51.7, 53.5, 59.6, 60.1, 65.2,
123.9, 126.8, 131.2, 140.2, 151.3, 156.7, 167.9, 169.9; IR (thin film)
H 9.31.
Minor (21): [R]25 -13.0 (c 1.2, CH2Cl2); H NMR (300 MHz,
1
D
CDCl3) δ 0.62 (s, 18H), 0.77 (s, 6H), 1.15 (s, 6H), 1.36 (s, 6H), 1.50-
1.90 (m, 10H), 2.69 (m, 2H), 3.59 (s, 6H), 3.73 (m, 10H), 3.81 (s,
6H), 3.95 (dd, J ) 9.6, 7.8, 2H), 7.59 (s, 2H); 13C NMR (75 MHz,
CDCl3) δ 20.6, 24.5, 25.5, 26.1, 27.2, 33.8, 39.2, 41.2, 45.1, 51.8, 59.5,
60.1, 67.8, 76.7, 122.1, 125.2, 131.4, 139.3, 151.8, 154.9, 163.0; IR
3305(br), 1726, 1652 cm-1
.
Diol 27 was prepared from the (R)-valinol derived bisacetamide, by
the same procedure used to prepare 24, in 96% yield as an amorphous
1
solid: [R]25 -70.2 (c 1.1, CHCl3); H NMR (300 MHz, CDCl3) δ
D
(thin film) 1654 cm-1
.
0.71 (s, 6H), 1.13 (s, 6H), 1.40 (s, 6H), 1.50-1.90 (m, 12H), 2.53 (bs,
2H), 2.80 (m, 2H), 3.55 (s, 6H), 3.78 (s, 6H), 4.22 (bs, 4H), 7.26 (s,
2H); 13C NMR (75 MHz, CDCl3) δ 20.6, 24.5, 25.2, 27.1, 38.6, 40.8,
45.2, 51.9, 59.9, 60.4, 63.7, 126.1, 128.2, 133.8, 140.7, 150.9, 152.8;
IR (thin film) 3289(br) cm-1. Anal. Calcd for C34H50O6: C 73.61, H
9.08. Found: C 73.62, H 9.23.
(26) (a) Hirsch, J. A. Top. Stereochem. 1967, 1, 199. (b) Eliel, E. L.;
Manoharan, M. J. Org. Chem. 1981, 46, 1959. (c) Allinger, N.; Freiberg,
L. J. Org. Chem. 1966, 31, 804.
(27) Fuson, R. C.; Cleveland, E. A. Organic Syntheses; Wiley: New
York, 1955; Vol. III, p 339.

Syntheses of Mastigophorenes A and B
J. Am. Chem. Soc., Vol. 121, No. 12, 1999 2769
(-)-Mastigophorene A, 2. To a stirred solution of diol 24 (40 mg,
0.072 mmol) in THF (1.5 mL) were added PPh3 (45 mg, 0.17 mmol)
and CBr4 (60 mg, 0.18 mmol) in one portion. After 30 min, TLC still
showed additional starting material, so additional PPh3 (38 mg, 0.14
mmol) and CBr4 (48 mg, 0.14 mmol) were added in one portion. After
10 min, the solution was quenched by addition of MeOH, concentrated,
and filtered through silica, eluting with CH2Cl2. The crude dibromide
was dissolved in ether (1.5 mL) and treated with LiAlH4 (1 M in ether,
0.5 mL, 0.5 mmol). The solution was stirred for 2 h and quenched by
cautious addition of MeOH and then 20% aqueous KOH. The white
precipitate was filtered. Column chromatography (2% EtOAc/Hex) of
mastigophorene A (en route to 2) in 89% yield as a crystalline solid:
1
[R]25 -26.2 (c 1.1, CHCl3); H NMR (300 MHz, CDCl3) δ 0.70 (s,
D
6H), 1.12 (s, 6H), 1.40 (s, 6H), 1.50-1.85 (m, 10H), 1.90 (s, 6H),
2.70 (m, 2H), 3.56 (s, 6H), 3.76 (s, 6H), 6.95 (s, 2H); 13C NMR (75
MHz, CDCl3) δ 19.9, 20.7, 24.4, 25.5, 27.1, 39.0, 41.1, 45.2, 51.7,
59.7, 60.3, 125.3, 130.0, 130.3, 139.1, 151.1, 151.3.
Next, 3 was prepared from tetramethylmastigophorene B by the
action of BBr3 (10 equiv), utilizing the same procedure used to prepare
1
1, in 90% yield: [R]25 +38.0 (c 0.35, CHCl3); H NMR (300 MHz,
D
CDCl3) δ 0.79 (s, 6H), 1.21 (s, 6H), 1.47 (s, 6H), 1.50-1.80 (m, 10H),
1.92 (s, 6H), 2.62 (m, 2H), 4.76 (s, 2H), 5.58 (s, 2H), 6.85 (s, 2H); 13
C
the eluent gave 33 mg (88%) of tetramethylmastigophorene A as a
1
crystalline solid: mp 154-156 °C; [R]25 +8.68 (c 1.5, CHCl3); H
D
NMR (75 MHz, CDCl3) δ 19.2, 20.6, 22.6, 25.7, 27.2, 39.2, 41.3, 45.0,
NMR (300 MHz, CDCl3) δ 0.70 (s, 6H), 1.13 (s, 6H), 1.41 (s, 6H),
1.45-1.85 (m, 10H), 1.94 (s, 6H), 2.68 (m, 2H), 3.56 (s, 6H), 3.76 (s,
6H), 6.95 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 20.1, 20.7, 24.2, 25.5,
27.1, 39.0, 41.1, 45.2, 51.7, 59.7, 60.2, 125.1, 129.8, 130.7, 139.2, 151.1,
151.3.
51.4, 117.1, 122.7, 126.8, 133.9, 140.7, 141.6; IR (thin film) 3531,
2961, 1226 cm-1
.
Acknowledgment. The authors are grateful to the National
Science Foundation and the National Institute of Health for
financial support of this work. A fellowship (A.P.D.) from
Boehringer-Ingelheim is also gratefully acknowledged.
Next, 2 was prepared from tetramethylmastigophorene A by the
action of BBr3 (10 equiv), utilizing the same procedure used to prepare
1
1, in 84% yield: [R]25 -67.6 (c 0.4, CHCl3); H NMR (300 MHz,
D
CDCl3) δ 0.78 (s, 6H), 1.19 (s, 6H), 1.44 (s, 6H), 1.45-1.85 (m, 10H),
1.92 (s, 6H), 2.67 (m, 2H), 4.69 (s, 2H), 5.56 (s, 2H), 6.84 (s, 2H); 13
C
Supporting Information Available: Spectral data (1H and
13C NMR) of all key intermediates and final products (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
NMR (75 MHz, CDCl3) δ 19.3, 20.5, 22.8, 25.6, 27.2, 38.9, 41.2, 45.0,
51.4, 116.9, 122.8, 126.7, 133.9, 140.5, 141.6; IR (thin film) 3526,
2958, 1222 cm-1. Anal. Calcd for C30H42O4‚2/3H2O:4 C 75.27, H 9.12.
Found: C 75.60, H 9.08.
(-)-Mastigophorene B, 3. Tetramethylmastigophorene B was
prepared from 27 by the same procedure used to prepare tetramethyl-
JA984182X