Synthesis of Petrosins C and D

Article abstract of DOI:10.1021/jo9801770

Petrosins C and D (5 and 6), diastereomers of the known natural products petrosin (1), petrosin A (2), and petrosin B (3), have been prepared. The synthetic route involved initial creation of a 16-membered bis-pyridine intermediate, exemplified by compounds 7, 28, and 52. Several different methods for formation of the macrocycle were evaluated, and the most efficient (Schemes 7-9) involved use of Z double bonds in the six-carbon chains linking the two pyridine rings. This approach permitted the two pyridine subunits (37 and 39) to be joined by alkylation of a lithiated α-methylpyridine with an allylic chloride (e.g., 37 + 39 → 40 and 49 → 45). Bisannulation of compounds 7 and 28 was complicated by a surprising lack of acidity of the α-pyridyl methylene groups Eventually, this problem was solved by stepwise introduction of two allyl groups, using the more acidic sulfone for introduction of the first (e.g., 52 → 53) and direct allylation to introduce the second (e.g., 54 → 55 + 56). The bisannulation was completed by hydroboration and conversion of the primary alcohols into methanesulfonate derivatives, which cyclized to afford bis-pyridinium derivatives. Reduction of these intermediate salts with sodium borohydride provided crystalline bis-enol ethers (60 and 63) and the relative configuration was established by single-crystal X-ray analysis of 63. After hydrolysis of the enol ethers to the corresponding ketones, the syntheses of 5 and 6 were completed by enolate methylation. As expected, compounds 5 and 6 do not form imine derivatives when treated with primary amines, presumably because of A^1,3 strain.

Full text of DOI:10.1021/jo9801770

J . Org. Chem. 1998, 63, 5013-5030
5013
Syn th esis of P etr osin s C a n d D
Clayton H. Heathcock,* Richard C. D. Brown, and Thea C. Norman
Department of Chemistry, University of California, Berkeley, California 94720
Received February 2, 1998
Petrosins C and D (5 and 6), diastereomers of the known natural products petrosin (1), petrosin A
(2), and petrosin B (3), have been prepared. The synthetic route involved initial creation of a 16-
membered bis-pyridine intermediate, exemplified by compounds 7, 28, and 52. Several different
methods for formation of the macrocycle were evaluated, and the most efficient (Schemes 7-9)
involved use of Z double bonds in the six-carbon chains linking the two pyridine rings. This approach
permitted the two pyridine subunits (37 and 39) to be joined by alkylation of a lithiated
R-methylpyridine with an allylic chloride (e.g., 37 + 39 f 40 and 49 f 45). Bisannulation of
compounds 7 and 28 was complicated by a surprising lack of acidity of the R-pyridyl methylene
groups. Eventually, this problem was solved by stepwise introduction of two allyl groups, using
the more acidic sulfone for introduction of the first (e.g., 52 f 53) and direct allylation to introduce
the second (e.g., 54 f 55 + 56). The bisannulation was completed by hydroboration and conversion
of the primary alcohols into methanesulfonate derivatives, which cyclized to afford bis-pyridinium
derivatives. Reduction of these intermediate salts with sodium borohydride provided crystalline
bis-enol ethers (60 and 63) and the relative configuration was established by single-crystal X-ray
analysis of 63. After hydrolysis of the enol ethers to the corresponding ketones, the syntheses of
5 and 6 were completed by enolate methylation. As expected, compounds 5 and 6 do not form
imine derivatives when treated with primary amines, presumably because of A1,3 strain.
Sch em e 1
In the previous paper in this issue, we reported the
total synthesis of the marine alkaloid petrosin (1).1 This
synthesis also provided synthetic samples of the natural
products petrosin A (2) and petrosin B (3), as well as the
previously unknown diastereomer petrosin B′ (4). In this
paper, we report the synthesis of two other diastereomers
that have not yet been found in nature, petrosin C (5)
and petrosin D (6).
Our plan for the synthesis of compounds 5 and 6 is
summarized in Scheme 1. We thought that if we could
prepare the symmetrical, achiral macrocyclic bis-pyridine
7, we might be able to convert it to bis-enones 8 and 9.
These two diastereomers might then be individually
converted into petrosins C and D by reduction of the two
double bonds and introduction of the two methyl groups
by enolate alkylation. This plan also appeared to offer
hope of stereocontrol. First, it might be possible to
control the stereoselectivity of the annulations leading
from 7 to 8 and 9. Alternatively, it might be possible to
equilibrate these diastereomers under basic conditions.
Indeed, molecular mechanics global minimization studies
suggested a significant difference in energy of the two
isomers; Monte Carlo conformational searches using
Marcomodel and the MM2 force field found low-energy
conformations of 8 and 9 with energies of -15.2 and -8.2
kJ /mol, respectively. Furthermore, reduction the two
double bonds in each case should be controlled by the
(1) Scott, R. W.; Epperson, J . E.; Heathcock, C. H. J . Org. Chem.
1998, 63, xxxx.
S0022-3263(98)00177-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/26/1998

5014 J . Org. Chem., Vol. 63, No. 15, 1998
Heathcock et al.
Sch em e 2a
a
Key: (a) PhSO2CH2Cl, NaOH, DMSO; (b) NaOMe, MeOH, rt; (c) (i) n-BuLi, THF; (ii) CH2dCHCH2Br; (d) 6% Na/Hg, Na2HPO4,
MeOH; (e) OsO4, NaIO4, THF, H2O; (f) CH2dCHMgBr, THF; (g) TBSCl, Et3N, DMAP, CH2Cl2; (h) m-CPBA, CH2Cl2; (i) p-TsCl, Et3N,
CH2Cl2; (j) NaSO2Ph, DMF.
Sch em e 3a
a
Key: (a) Ac2O, Et3N, DMAP, CH2Cl2; (b) m-CPBA, CH2Cl2; (c) p-TsCl, Et3N, CH2Cl2; (d) NaSPh, DMF.
adjacent C-6 stereocenter, with addition of hydrogen to
C-5 coming from the face trans to the methylene sub-
stituent at C-5. With the relative configurations of C-5
and C-6 established in this manner, simple keto-enol
equilibration would provide the correct relative configu-
rations at C-2 and C-4.
Ash and Pews, wherein a picoline N-oxide is treated with
a halogenating agent.4 To this end, the N-oxide 18 was
prepared in quantitative yield and treated with p-
toluenesulfonyl chloride, followed by sodium benzene-
sulfenate to obtain sulfone 19 in modest yield. Prepa-
ration of a coupling partner to use with 19 is shown in
Scheme 3. Allylic alcohol 16 is acetylated to give 20,
which is subjected to a similar procedure to functionalize
the methyl group, except that the chloromethyl interme-
diate is treated with sodium thiophenoxide to obtain
sulfide 22.
To join sulfone 19 and allyl acetate 22, we employed
Trost’s Pd(0) method, whereby the sulfone anion attacks
a π-allylpalladium (Scheme 4).5 Treatment of 19 with a
slight excess of sodium hexamethyldisilazane in THF
gives the anion, which is added slowly to a THF solution
of allylic acetate 22 and 4 mol % of Pd(dba)2‚CHCl3. The
coupled product, 23, is obtained in this manner in good
yield. Reductive desulfonylation followed by desilylation
provides allylic alcohol 24. This is acylated by treatment
with pivalic anhydride to obtain the allylic ester 25,
which is oxidized by tetrabutylammonium peroxymono-
sulfate (TBA-Oxone)6 to sulfone 26. This material is
appropriately constituted for application of a second Trost
alkylation to close the 16-membered central ring. Cy-
clization is accomplished by a similar protocol as was
used for joining the two fragments, except that the anion
formed by treatment of the sulfone with NaHMDS is
added to a refluxing solution of the palladium catalyst
with a syringe in order to achieve conditions of high
dilution. Scheme 4 shows that the cyclization does work
and gives the E,E diene 27 in 55% yield. Reductive
desulfonylation provides the symmetrical compound 28,
As shown in Scheme 2, the synthesis of bis-pyridine 7
began with application of Makosza’s “vicarious nucleo-
philic substitution” to the known2 2-methyl-4-nitropyri-
dine (10). Treatment of phenyl chloromethyl sulfone with
NaOH in DMSO, followed by addition of 10, affords the
substitution product. Makosza reports that this reaction
provides the 3-substituted product 11 in 60% yield.3 We
found that the reaction gives a 4.5:1 mixture of regioi-
someric sulfones in 94% total yield. A single recrystal-
lization from isopropyl alcohol gives the desired isomer
11 in 50% yield on a 50-g scale. Treatment of 11 with
sodium methoxide in methanol affords methyl ether 12
in 83% yield. Deprotonation of 12 with n-butyllithium
and addition of the resulting anion to excess allyl bromide
gives the alkylation product 13 in good yield. Although
compound 13 exists as a 2:1 mixture of rotamers on the
NMR time scale, reductive desulfonylation provides a
spectroscopically homogeneous product, 14. Cleavage of
the double bond occurs smoothly when 14 is treated with
sodium periodate and catalytic osmium tetraoxide. This
cleavage can also be accomplished by ozonolysis in
excellent yield on a small scale (27 mg, 85%) but in only
modest yield on a large scale (4.5 g, 64%). Aldehyde 15
reacts with vinylmagnesium bromide to provide allylic
alcohol 16, which is protected as the corresponding tert-
butyldimethylsilyl ether 17. To functionalize the methyl
group, we employed a method originally introduced by
(2) Wiley: R. H.; Hartman, J . L. J . Am. Chem. Soc. 1951, 73, 494.
(3) Makosza, M.; Chylinska, B.; Mudryk, B. Liebigs Ann. Chem.
1984, 8.
(4) Ash, M. L.; Pews, R. G. J . Heterocycl. Chem. 1981, 18, 939.
(5) Trost, B. M.; Verhoeven, T. R. J . Am. Chem. Soc. 1980, 102, 4743.
(6) Trost, B. M.; Breslau, R. J . Org. Chem. 1988, 53, 532.

Total Synthesis of Petrosins C and D
J . Org. Chem., Vol. 63, No. 15, 1998 5015
Sch em e 4a
a
Key: (a) (i) NaHDMS, THF; (ii) 22, 3.7 mol % Pd2(dba)2‚CHCl3, dppe, reflux; (b) Na/Hg, Na2HPO4, MeOH; (c) TBAF, THF; (d) (t-
BuCO)2O, Et3N, DMAP, CH2Cl2; (e) TBA-Oxone, CH2Cl2; (f) (i) NaHDMS; (ii) 12 mol % Pd2(dba)3‚CHCl3, dppe, THF, reflux; (g) AlHg,
THF, H2O; (h) H2, Raney Ni, MeOH.
Sch em e 5a
rotation about the indicated C-C bond. Reductive des-
ulfonylation of 29 cleanly affords the expected trisubsti-
tuted pyridine 30. Removal of the silyl protecting group
under acidic conditions gives an allylic alcohol that is
treated with methanesulfonyl chloride and lithium chlo-
ride in 2,6-lutidine to provide allylic chloride 31 about
80% yield for the two steps. This material is prone to
polymerization, and it is necessary to use it immediately
in the following step.
Compound 30 is metalated with n-butyllithium and the
resulting anion treated with freshly prepared chloride 31
to obtain 32 in excellent yield (Scheme 6). The pyridine
methyl group is functionalized by regioselective metala-
tion with n-butyllithium and treatment of the derived
lithiated intermediate with diphenyl disulfide; thioether
33 is obtained in 73% yield. Removal of the silyl
protecting group and acylation of the resulting allylic
alcohol with pivaloyl chloride provides 34, which is
oxidized by TBA-Oxone to obtain sulfone 35 in moderate
yield. To close the macrocycle, we again used the Trost
Pd(0) methodology. To this end, sulfone 35 is treated
sequentially with sodium hexamethyldisilazane and 4
mol % of Pd(dba)2‚CHCl3. In this manner, the macrocycle
27 is obtained in 74% yield as a 2.5:1 mixture of E,E and
E,Z isomers. This stereochemical outcome is consistent
with the intermediacy of rapidly equilibrating E and Z
π-allylpalladium intermediates, which undergo ring clo-
sure at different rates to afford the observed isomeric
mixture.7 Normally the E π-allylpalladium species is
a
Key: (a) (i) n-BuLi, THF; (ii) (E)-ClCH2CHdCHCH2OTBS; (b)
5% Na/Hg, MeOH; (c) 1 N HCl, THF; (d) MsCl, lutidine, LiCl,
DMF.
and hydrogenation of 27 provides the bis-pyridine 7.
Later work (vide infra) revealed that the cyclization
reaction had actually produced 27 and its E,Z isomer in
a 2:1 ratio, in a total yield of about 80%, and that we
had missed the minor isomer in the chromatographic
separations.
Although successful in delivering the desired macro-
cyclic bis-pyridine, the foregoing route proved to be
difficult to scale-up, and we decided to develop a some-
what more convergent version. In addition, we thought
we might be able to replace at least one and possibly both
of the palladium-mediated alkylations by more low-tech
methods. As shown in Scheme 5, alkylation of sulfone
12 with the tert-butyldimethylsilyl ether of (E)-4-chlo-
robut-2-en-1-ol provides sulfone 29 in high yield. Once
again, compound 29 shows NMR evidence of restricted
(7) (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1989, 28, 1173. (b)
Godleski, S. A. In Comprehensive Organic Synthesis; Trost, B. M.;
Fleming, I.; Semmelhack, M. F., Eds; Pergamon Press: Oxford, 1991;
Vol. 4, Chapter 3.3, pp 585-562.

5016 J . Org. Chem., Vol. 63, No. 15, 1998
Heathcock et al.
Sch em e 6a
Key: (a) n-BuLi, 31; (b) (i) n-BuLi; (ii) PhSSPh; (c) TBAF; (d) Me3CCOCl; (e) Bu4N+HSO5-; (f) (i) NaHDMS; (ii) 6 mol % Pd2(dba)3‚CHCl3,
a
dppe, THF, reflux.
Sch em e 7a
a
Key: (a) (i) n-BuLi, THF; (ii) (Z)-ClCH2CHdCHCH2OTBS; (b) 5% Na/Hg, MeOH; (c) 1 N HCl, THF; (d) MsCl, lutidine, LiCl, DMF.
strongly favored in such equilibria. The observation of
so much of the E,Z diene in this cyclization may indicate
that the Z isomer cyclizes significantly faster than the E
isomer.
prepared and immediately used for alkylation. Following
the previously developed route, the Z allylic TBS ether
37 was lithiated and the resulting anion treated with
chloride 39. This procedure delivers the coupled product
40 in high yield (Scheme 8). Some problems were
encountered in thiolating the methyl group of 40 when
the reaction was carried out as in the preparation of the
E,E isomer 32 (see Scheme 6). When the alkylation was
carried out on the lithiated methylpyridine, the yield of
desired product was variable and the product was usually
contaminated with significant amounts of the bissulfi-
nylated product. This problem was completely elimi-
nated if the initial lithiated methylpyridine was trans-
metalated to the magnesium derivative by addition of
MgBr2-etherate before addition of the diphenyl disulfide.
In this manner, thioether 41 may be prepared on a
multigram scale in more than 70% yield. Removal of the
silyl protecting group provides allylic alcohol 42, which
is converted into the corresponding pivalate 43 in stan-
dard fashion. Oxidation of the sulfide to the correspond-
ing sulfone 44 proceeds in very high yield using ammo-
nium molybdate and hydrogen peroxide. The sodium salt
of the Z,Z substrate 44 was cyclized by treatment with
2.5 mol % of Pd(dba)2‚CHCl3. As with the E,Z isomer,
cyclization occurred in good yield, and once again, a
mixture of double-bond isomers was produced. In this
case, the ratio of E,Z isomer 46 and Z,Z isomer 45 was
variable, ranging from 2:1 to 5:1 (always favoring the E,Z
isomer). The isomer ratio tended to be dependent on the
Although this route did provide the desired marcocyclic
sulfone in better overall yield, and did eliminate one of
the Pd-mediated alkylations, (E)-ClCH2CHdCHCH2-
OTBS is difficult to prepare on a large scale. Further-
more, the production of a mixture of double-bond isomers
in the cyclization reaction limited some of our options,
particularly the possibility of leaving these double bonds
in place until after the double-annulation process sug-
gested in Scheme 1. We thought that both these prob-
lems might be alleviated by using Z double bonds in the
linking chains, which necessitated the preparation of (Z)-
ClCH2CHdCHCH2OTBS. This was conveniently pre-
pared in about 70% overall yield on a 25-30 g scale using
literature procedures.8 As shown in Scheme 7, the Z
allylic chloride was employed in the same manner as
previously used for the E isomer to alkylate lithiated
sulfone 36. Once again, the alkylation product (36) was
obtained in excellent yield and as a mixture of rotamers
on the NMR time scale. Desulfonylation of this mixture
provides a homogeneous substance, 37, which is con-
verted by way of alcohol 38 into the Z allylic chloride 39.
Like its E isomer, chloride 39 is prone to polymeriza-
tion if stored for any length of time, so it was freshly
(8) (a) McDougal, P. G.; Rico, J . G.; Oh, Y.-I., Condon, B. J . Org.
Chem. 1986, 51, 3388. (b) Collington, E. W.; Meyers, A. I. J . Org. Chem.
1971, 36, 3044.

Total Synthesis of Petrosins C and D
J . Org. Chem., Vol. 63, No. 15, 1998 5017
Sch em e 8a
a
Key: (a) (i) n-BuLi, THF; (ii) 39; (b) (i) n-BuLi, THF; (ii) MgBr2‚Et2O; (iii) PhSSPh; (c) 1 N HCl, THF; (d) Piv-Cl, Et3N, DMAP,
CH2Cl2; (e) (NH4)6Mo7O24, H2O2; (f) (i) NaHDMS; (ii) 6 mol % Pd2(dba)3‚CHCl3, dppe, THF, reflux.
Sch em e 9a
a
Key: (a) (NH4)6Mo7O24, H2O2; (b) 1 N HCl, THF; (c) MsCl, LiCl, 2,6-lutidine, DMF; (d) NaHMDS, THF.
scale at which the reaction was carried out. It is possible
that in this case the rate of isomerization of the Z and E
π-allylpalladium is comparable with the rate of cycliza-
tion. Because the allyl pivalate is Z, the first-formed
π-allylpalladium presumably has the Z configuration, and
this isomer is expected to equilibrate to the more stable
E isomer. However, if the cyclization is more rapid in
this case than it is with the isomer used previously (see
Scheme 4), some cyclization may occur before equilibra-
tion of the π-allylpalladium intermediates has been fully
established.
gether. To this end, as shown in Scheme 9, sulfide 41
was oxidized to sulfone 47, which was deprotected to
obtain Z allylic alcohol 48. Treatment of this material
with methanesulfonyl chloride and lithium chloride in a
mixture of 2,6-lutidine and dimethylformamide afforded
the unstable allylic chloride 49. Cyclization was ac-
complished by the method suggested by Keinan and co-
workers,9 whereby a solution of 49 is added by syringe
pump to a refluxing solution of sodium hexamethyldisi-
lazane in tetrahydrofuran. This procedure provided the
Z,Z macrocyclic sulfone 45 in greater than 80% overall
yield for the two-step sequence. This discovery greatly
Because the macrocyclization seemed somewhat more
facile in the Z,Z series, it seemed possible that we might
be able to forego the Pd-catalyzed methodology alto-
(9) Keinan, E.; Sinha, S. C.; Sinha-Bagchi, A. J . Chem. Soc., Perkin
Trans. 1 1991, 3333.

5018 J . Org. Chem., Vol. 63, No. 15, 1998
Heathcock et al.
Sch em e 10a
Sch em e 11
a
Key: (a) (i) 2.7 equiv of n-BuLi, THF, (ii) BrCH2CH2CH2Cl;
(b) NaI, acetone, reflux; (c) L-Selectride, THF.
facilitated the scale-up of this synthesis, especially in that
the direct cyclization of chloride 49 actually worked better
as the scale was increased, in contrast to the Pd(0)-
mediated cyclization, which tended to give lower yields
on scale-up.
shown in Scheme 11, deprotonation of 2-ethyl-4-meth-
oxypyridine can give two isomeric lithiated derivatives,
(E)- and (Z)-51-Li. Because the acidic methylene groups
of 7 are in a ring, it is likely that only one lithiated
derivative, (E)-7-Li, can be formed. This derivative is
subject to severe A1,3 strain, as indicated in Scheme 11.
The situation would be greatly exacerbated in the forma-
tion of the dilithiated derivative because of the necessity
of creating a dianion, both of which would suffer from
A1,3 strain.
With a good synthesis to the 16-membered ring bis-
pyridine worked out, we were able to turn our attention
to the proposed bisannulation set forth in Scheme 1.
Unsaturated sulfone 27 was easily converted into 7 by
desulfonylation with aluminum amalgam, followed by
catalytic hydrogenation over Raney nickel, as shown in
Scheme 4. However, our initial attempts to generate the
bis-quinolizidone framework met with no success. We
had hoped to exploit the well-known acidity of the
position R to the pyridine ring to generate a dianion from
7. However, treatment of 7 with 2 or more equiv of
various strong bases, followed by 1,3-dibromopropane,
gave no evidence of a diakylated product. In an early
experiment, we treated 28 with excess n-butlyllithium
in THF and then added 1-bromo-3-chloropropane to the
resulting anion. After treatment of the resulting salt
with sodium iodide in refluxing acetone (to exchange the
primary chloride for iodide), we obtained a polar product
that was taken up in THF and treated with L-Selectride.
This treatment provided quinolizidone 50 in 50% yield
(Scheme 10). The formation of a mono-annulated product
in this process suggests that 28 only undergoes mono-
lithiation, even though an excess of n-butyllithium was
used.
Fortunately, the presence of the sulfone on the mac-
rocycle provides a handle that we hoped to be able to use
to introduce the side chains in a stepwise fashion. The
desired sulfone 52 was prepared by diimide reduction of
the macrocyclic diene 45 as hydrogenation over Raney
Ni proved to be unreliable, slow, and relatively low
yielding. The seemingly trivial alkylation of the sulfone
52 was not straightforward due to its low nucleophilicity.
Only highly reactive electrophiles such as allyl bromide
(required HMPA) and methyl iodide would react with the
lithiated sulfone at a useful rate. Although allylation of
52 in THF-HMPA (2:1) with allyl bromide provided the
desired product 53 in a respectable 60-70% yield,
separation of unreacted starting sulfone from HMPA was
tedious and time consuming. This technical problem was
solved in a most unusual waysby using 2,6-lutidine as
a cosolvent. This solvent displayed a number of virtues:
(i) it is readily removed under high vacuum, (ii) it
enhances the reactivity of the sulfone anion sufficiently
to react with allyl iodide rapidly at room temperature,
(iii) the solubility of sulfone 52 in THF-2,6-lutidine is
significantly greater than in THF-HMPA, and (iv) the
acidity of the 2,6-lutidine (pKa around 34.5 in THF)10
allows an excess of n-BuLi to be used to deprotonate the
sulfone, the excess removing a proton from the 2,6-
lutidine, ensuring complete deprotonation of sulfone and
providing a “buffering” effect. Under the conditions
shown in Scheme 12, the desired allylated product 53 was
obtained in over 90% yield. Reductive desulfonylation
proceeded cleanly to provide 54.
To test the proposed dianion formation, we treated 7
with n-butyllithium, sec-butyllithium, or tert-butyllithium
in various solvents (THF, THF-HMPA, THF-TMEDA)
and quenched with excess methyl iodide to measure the
extent of deprotonation. Although evidence for mono-
lithiation was obtained, exhaustive studies failed to
provide a synthetically useful method to generate the
dianion. We believe failure to generate the dianion can
be attributed to the reduced kinetic acidity of the mac-
rocycle 7, combined with its very low solubility in
appropriate solvents (7 is only marginally soluble in THF,
1,4-dioxane, THF-HMPA, or toluene and is virtually
insoluble in ether or hexane). Qualitative evidence for
the reduced kinetic acidity of 7 was provided by deuterium-
exchange experiments in D3COD/D3CONa at elevated
temperatures. Very little or no deuterium incorporation
was seen, even after extended periods. In contrast,
2-ethyl-4-methoxypyridine (51) showed substantial deu-
terium incorporation under the same conditions. This
reduced acidity may be due to the cyclic nature of 7. As
To introduce the second three-carbon unit, compound
54 was deprotonated with s-BuLi and TMEDA and the
(10) Fraser, R. R.; Breese, M.; Mansour, T. S. J . Chem. Soc., Chem.
Commun. 1983, 620.

Total Synthesis of Petrosins C and D
J . Org. Chem., Vol. 63, No. 15, 1998 5019
Sch em e 12a
a
Key: (a) p-TsNHNH2, NaOAc, THF, H2O; (b) (i) 3 equiv of n-BuLi, 2,6-lutidine, THF; (ii) CH2dCHCH2I; (c) Na/Hg, THF, MeOH; (d)
(i) s-BuLi, TMEDA, ether, (ii) CH2dCHCH2Br.
Sch em e 13a
a
Key: (a) (i) 9-BBN, THF, (ii) H2O2; (b) MsCl, Et3N, CH2Cl2; (c) NaBH4, EtOH; (d) aqueous HCl.
resulting anion treated with allyl bromide. The dially-
lated macrocycles 55 and 56 were conveniently separated
by radial chromatography on silica, along with two
byproducts (57 and 58) and recovered starting material.
The presence of byproduct 57 implies that the pyridine
ring was metalated, again illustrating the rather harsh
conditions required to deprotonate at the desired position.
Fortunately, bromopyridine 57 was easily recycled by
halogen-metal exchange followed by protonation.
To close the quinolizidone rings, we needed to function-
alize the allyl side chains. We thought that a sequence
of hydroboration and activation of the resulting alcohol
would provide the desired dipyridinium salt. However,
hydroboration of diene 56 with BH3‚DMS led to an
unexpectedly complex mixture of products that contained
mixtures of secondary alcohols in addition to the desired
primary alcohols. Isolation of the desired diol 62 from
the reaction mixture proved to be very difficult and
required derivatization of the mixture with acetic anhy-
dride followed by several chromatographic separations.
The two diastereomers 55 and 56 were taken through
the final steps of the synthesis separately (Scheme 13).

5020 J . Org. Chem., Vol. 63, No. 15, 1998
Heathcock et al.
F igu r e 1. Portions of the 1H NMR spectra of petrosin C (5) and petrosin D (6).
Sch em e 14a
However, hydroboration with 9-BBN provided a much
cleaner reaction, yielding desired diol 62 in almost 80%
yield. However, significant amounts of what were thought
to be secondary alcohols were still present. Again,
purification of the diol 62 by chromatography proved to
be very difficult. Fortunately, it was possible to crystal-
lize most of the desired diol 62 from the reaction mixture.
The rather unusual regioselectivities and reactivities
observed during the hydroboration of diene 56 are
probably due to the presence of the pyridine nitrogen in
the proximity of the olefin. Similar hydroboration of the
minor diallylated product 55 provided diol 59.
Activation of the diols 59 or 62 with methanesulfonyl
chloride resulted in smooth cyclization to stable dipyri-
dinium salts. We were not able to reduce these pyri-
dinium salts with L-Selectride in THF as we had in
several previous models. This is almost certainly due to
the insolubility of the dication, rather than a reactivity
problem as both the bicyclic model compound and the
monoannulated macrocycle 50 (Scheme 10) were pre-
pared in this way. In contrast, reduction with NaBH4
in ethanol provided the dienol ethers 60 and 63, which
were difficult to purify by chromatography. Gratifyingly,
like all of the macrocycles encountered in this work, these
reduction products can be purified by recrystallization
and obtained in about 70% yield. The structure of diether
a
Key: (a) LDA, THF, MeI; (b) K2CO3, MeOH, H2O.
60 was elucidated by single-crystal X-ray analysis. Hy-
drolysis of the dienol ethers 60 and 63 cleanly provided
diketones 61 and 64.
their 13C NMR spectra. The H NMR are also simpler
than those of the unsymmetrical isomers, petrosins B and
B′. The most diagnostic region in the H NMR spectra
1
Clean dimethylation of diketone 64 proved to be quite
troublesome, especially on a small scale. When 64 was
treated with an excess of LDA, the dienolate precipitated
from solution, and introduction of methyl iodide followed
by very carefully monitoring of the reaction did allow
reasonable yields of the axially dimethylated product to
be obtained, along with starting material and some
polymethylated material. However, the insolubility of
the dienolate resulted in the reaction being very difficult
to control with an excess of base present. On a larger
scale (∼20 mg), when only 2 equiv of LDA was used, the
dimethylated product was obtained in good yield, and
equilibration with K2CO3 in methanol afforded the target,
petrosin D (6) (Scheme 14). Petrosin C (5) was obtained
in the same way, but the final dimethylation was never
achieved in good yield due to problems associated with
performing the dienolate chemistry on a small scale.
1
is the 2.4-3.2 ppm region. As shown in Figure 1, both
isomers display a characteristic broad triplet structure
at approximately 2.4 ppm. This resonance arises from
the axial proton at C-4, adjacent to the carbonyl group.
The two large coupling constants that are responsible for
the triplet appearance of this multiplet result from a
diaxial coupling to the bridgehead proton and one of the
protons in the linking five-carbon chain. The spectral
regions in Figure 1 should be compared with the corre-
sponding regions in the spectra of petrosin, petrosin A,
petrosin B, and petrosin B′.11
As expected, neither petrosin C nor petrosin D forms
an imine when treated with butylamine under conditions
that served to form imines from the mixture of petrosin
isomers reported in the previous paper in this issue.1 This
is understandable in terms of A1,3 strain, as shown by
the following structures:
The NMR spectra of petrosins C and D are in good
accord with their symmetrical structures. Because of
their symmetry, both isomers show only 15 signals in
(11) See Figure 3 in ref 1.

Total Synthesis of Petrosins C and D
J . Org. Chem., Vol. 63, No. 15, 1998 5021
(multiplet), br (broadened)], integration, and coupling constant-
(s) (Hz). 13C NMR spectra were recorded at 100 MHz with
proton decoupling using a Bruker AM-400. Distortionless
enhancement by polarization transfer (DEPT) was routinely
conducted to assist with signal assignments. Mass spectra
were recorded at U. C. Berkeley using fast atom bombardment,
or at Pfizer Central Research, Sandwich, Kent, U.K., using
atmospheric pressure chemical ionization.
2-Meth yl-4-n itr op yr id in e (10). A 100-mL flask equipped
with an addition funnel was charged with a solution of
2-methyl-4-nitropyridine N-oxide13 (2.50 g, 16.0 mmol) in
reagent-grade CHCl3 (53 mL) and was cooled to 0 °C. Phos-
phorus trichloride (7.0 mL, 80 mmol) was added dropwise to
the N-oxide solution from the addition funnel. The addition
was complete in 20 min, the ice bath was removed, and the
milky yellow solution was allowed to stir at room temperature
for 40 h. The mixture was poured onto ice and basified with
10% NaOH solution. Extraction with CHCl3 (3 × 40 mL),
drying (Na2SO4), and evaporation of the solvent provided a
crude material that was contaminated with POCl3. This
impurity was removed by washing an ether solution of the
crude produce with 10% HCl. The aqueous layer was collected
and carefully basified with 10% NaOH. Extraction with CH2-
Cl2, drying, and evaporation of the solvent provided a yellow
oil. Purification by flash chromatography on silica gel (2:98
methanol/CHCl3) afforded 1.9 g (84%) of 2-methyl-4-nitropy-
ridine (10) as a colorless solid. Mp: 43-44 °C (lit.2 mp 43-
44 °C). 1H NMR (400 MHz): δ 2.73 (s, 3), 7.83 (dd, 1, J ) 1.9,
5.3), 7.88 (d, 1, J ) 1.8), 8.79 (d, 1, J ) 5.4). 13C NMR (100
MHz): δ 24.43, 113.14, 115.39, 151.15, 153.94, 161.69.
2-Meth yl-4-n itr o-3-(ph en ylsu lfon ylm eth yl)pyr idin e (11).
To a stirring suspension of NaOH (2.12 g of Aldrich 20-40
mesh beads, 53.0 mmol) in reagent-grade DMSO (17 mL)
cooled to 15 °C (cold water bath) was added a solution of
chloromethyl phenyl sulfone (2.54 g, 13.3 mmol) and nitropy-
ridine 10 (1.86 g, 13.3 mmol) in DMSO (22 mL) dropwise with
a Teflon cannula, while the temperature was maintained below
20 °C. The intensely colored mixture (usually a cobalt blue)
was stirred vigorously for 30 min at 15-20 °C and was then
poured into a stirring solution of 1% HCl (200 mL, 66.0 mmol).
Chloroform (50 mL) was added to solubilize the organic
material. The aqueous layer was extracted with CHCl3 (3 ×
30 mL), and the combined organic extracts were washed
repeatedly with water to remove any DMSO. Drying (Na2-
SO4) of the organics and evaporation of the solvent provided
3.65 g (94%) of 10. Mp: 139-140 °C (lit.3 mp 141-142 °C).3
1H NMR (400 MHz): δ 2.66 (s, 3), 5.00 (s, 2), 7.53-7.79 (m,
6), 8.73 (d, 1, J ) 5.3). 13C NMR (100 MHz): δ 23.2, 53.5,
114.6, 115.7, 128.0, 129.4, 134.4, 150.8, 155.9, 162.3.
4-Met h oxy-2-m et h yl-3-[(p h en ylsu lfon yl)m et h yl]p yr i-
d in e (12). Sodium methoxide was prepared by adding small
pieces of Na (2.2 g, 96 mmol) to precooled (0 °C) reagent-grade
methanol (70 mL). Nitropyridine 11 (18.8 g, 64.0 mmol) was
dissolved in methanol (60 mL) and added dropwise to the
NaOMe solution. The resulting deep red solution was stirred
at room temperature overnight and was then neutralized with
aqueous NH4Cl. The reaction mixture was partitioned be-
tween CHCl3 and aqueous NH4Cl, and the aqueous layer was
extracted with CHCl3 (3 × 70 mL). The combined organic
extracts were dried (Na2SO4), and the solvent was removed
with a rotary evaporator. The remaining residue was chro-
matographed on silica gel (1:99 methanol/CHCl3) to afford 14.8
g (83%) of methoxypyridine 12. 1H NMR (400 MHz): δ 2.53
(s, 3), 3.28 (s, 3), 4.48 (s, 2), 6.40 (d, 1, J ) 5.7), 7.39-7.63 (m,
5), 8.25 (d, 1, J ) 5.7). 13C NMR (125 MHz): δ 15.24, 53.45,
55.71, 105.21, 114.96, 128.50, 128.77, 133.87, 138.10, 139.97,
150.55, 155.15. Anal. Calcd for C14H15NO3: C, 60.65; H, 5.41;
N, 5.05. Found: C, 60.41; H, 5.34; N, 5.09.
The mixture of diastereomers resulting from the double
Mannich cyclization1 consisted principally of petrosin,
petrosin A, petrosin B, and petrosin B′. Each of these
isomers has at least one quinolizidone that can form an
imine without A1.3 strain:
Thus, the following equilibrations are possible via the
intermediate imines: petrosin with petrosin A and
petrosin B with petrosin B′. Since petrosin A is achiral
(meso), this could account for the fact that natural
petrosin is racemic. Since both petrosin B and petrosin
B′ are chiral, equilibrating them would not give rise to a
racemic natural product. It follows that, if petrosins C
and D are eventually found in natural sources, they will
probably be enantiomerically pure.
Exp er im en ta l Section
Gen er a l Meth od s. All moisture- or air-sensitive reactions
were carried out under an atmosphere of nitrogen or argon in
oven-dried glassware. All reagents and solvents were used
as obtained from commercial suppliers except for the follow-
ing: THF and diethyl ether were freshly distilled from
sodium-benzophenone ketyl. Benzene, methylene chloride,
diisopropylamine, and triethylamine were freshly distilled
from CaH2 prior to use. 2,6-Lutidine was distilled from CaH2
and stored over KOH pellets. DMF and HMPA were distilled
from CaH2 and stored over 4 Å molecular sieves. Mesyl
chloride was distilled. Allyl bromide, allyl iodide, and methyl
iodide were passed through a plug of basic alumina im-
mediately prior to use. Organolithium reagents and NaHMDS
were regularly titrated against 2,6-di-tert-butyl-4-methylphe-
nol using fluorene to determine the end point.
Purification on silica refers to “flash chromatography”, which
was adapted from the procedure described by Still et al.12
Column dimensions are given as height × width (cm). Either
Merck silica gel (230-400 mesh) or Fischer basic alumina,
activity 1,60-325 mesh, was used as the stationary phase.
Solvents were of HPLC quality and were used as supplied.
Thin-layer chromatography (TLC) analysis was used to moni-
tor the progress of all reactions. Merck silica gel 60 F254 coated
glass plates were used, visualizing with long-wave ultraviolet
illumination, iodine vapor, or ceric ammonium molybdate
stain.
Melting points are uncorrected in open-ended capillaries
except when a sealed tube is specified, “sealed tube” refers to
a capillary tube sealed under vacuum. IR spectra were
recorded on Mattson Gemini or Nicolet Magna 550 FTIR
spectrometers from thin films or from solutions in the solvent
specified. 1H NMR spectra were recorded using Bruker AM-
instruments at 400 or 500 MHz in CDCl3, and chemical shifts
are reported in ppm relative to internal CHCl3 (7.27 ppm). 1H
NMR data are described in the following order: chemical shift,
multiplicity [s (singlet), d (doublet), t (triplet), q(quartet), m
4-Meth oxy-2-m eth yl-3-[1-(p h en ylsu lfon yl)-3-bu ten yl]-
p yr id in e (13). A solution of pyridine 12 (1.30 g, 4.67 mmol)
in freshly distilled THF (15 mL) cooled to -78 °C was treated
(13) 2-Methyl-4-nitropyridine N-oxide was obtained from the Aldrich
Chemical Co., catalog no. 45,485-0.
(12) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

5022 J . Org. Chem., Vol. 63, No. 15, 1998
Heathcock et al.
with n-butyllithium (3.09 mL of a 1.66 M solution in hexanes,
5.14 mmol). The resulting yellow solution was stirred for 1 h
at -78 °C, warmed to 0 °C for 45 min, and then recooled to
-78 °C. The yellow anionic solution was then added with a
cannula to cooled (0 °C) neat allyl bromide (4.04 mL, 46.0
mmol). Once the addition was complete, the reaction was
stirred for 1.25 h and quenched with a saturated NH4Cl
solution. The neutralized mixture was transferred to a sepa-
ratory funnel, extracted with ether (3 × 25 mL), and washed
with a saturated NaCl solution. The combined organic ex-
tracts were dried (Na2SO4), and the solvent was removed with
a rotary evaporator. The residue was chromatographed on
silica gel (1.5:98.5 methanol/CHCl3) to afford 1.35 g (91%) of
was quenched with a saturated NH4Cl solution (60 mL) and
extracted with ethyl acetate (3 × 75 mL). The combined
organic extracts were dried (Na2SO4), and the solvent was
removed with a rotary evaporator. The residue was chromato-
graphed on silica gel (8:92 methanol/CHCl3) to afford 3.37 g
(81%) of 16 as a pale yellow oil. 1H NMR (400 MHz): δ 1.70
(q, 2, J ) 6.7), 2.52 (s, 3), 2.65 (br s, 1), 2.68-2.73 (m, 2), 3.87
(s, 3), 4.09 (q, 1, J ) 6.1), 5.10 (d, 1, J ) 9.2), 5.24 (d, 1, J )
15.8), 5.86-5.94 (m, 1), 6.62 (d, 1, J ) 5.8), 8.22 (d, 1, J )
5.8). 13C NMR (100 MHz): δ 21.42, 21.87, 35.72, 55.34, 72.31,
104.01, 114.58, 123.63, 140.84, 147.82, 157.31, 163.47. Anal.
Calcd for C12H17NO2: C, 69.54; H, 8.27; N, 6.76. Found: C,
69.45; H, 8.35; N, 6.48.
1
13 as a 67:33 mixture of rotamers (as observed by H NMR).
3-[3-(ter t-Bu tyld im eth ylsiloxy)-4-p en ten yl]-4-m eth oxy-
2-m eth ylp yr id in e (17). To allylic alcohol 16 (2.60 g, 12.0
mmol) diluted in freshly distilled CH2Cl2 (40 mL) was added
distilled triethylamine (3.02 mL, 21.6 mmol), tert-butyldim-
ethylsilyl chloride (2.83 g, 18.8 mmol), and a catalytic amount
of 4-(dimethylamino)pyridine. The mixture was stirred for 48
h at room temperature and was partitioned between CH2Cl2
and aqueous NH4Cl. The aqueous layer was extracted with
CH2Cl2 (3 × 30 mL), and the combined organic extracts were
washed with brine and dried (Na2SO4). The solvent was
removed with a rotary evaporator, and the remaining oil was
purified by flash chromatography (40:60 hexanes/ethyl ac-
etate), affording 3.17 g (82%) of allylic silyl ether 17 as a
colorless oil. 1H NMR (400 MHz): δ 0.06 (s, 3), 0.09 (s, 3),
0.93 (s, 9), 1.56-1.66 (m, 2), 2.48 (s, 3), 2.58-2.68 (m, 2), 3.82
(s, 3), 4.21 (m, 1), 5.09 (d, 1, J ) 10.4), 5.20 (d, 1, J ) 17.2),
5.86 (dddd, 1, J ) 17.1, 10.4, 5.7), 6.62 (d, 1, J ) 5.7), 8.22 (d,
1, J ) 5.7). 13C NMR (100 MHz): δ -4.90, -4.38, 18.24, 21.33,
21.96, 25.83, 36.58, 55.14, 73.54, 103.94, 113.84, 124.17,
141.16, 147.77, 157.16, 163.41. Anal. Calcd for C18H31NO2-
Si: C, 67.23; H, 9.71; N, 4.36. Found: C, 66.88; H, 9.86; N,
4.54.
3-[3-(ter t-Bu tyld im eth ylsiloxy)-4-p en ten yl]-4-m eth oxy-
2-m eth ylp yr id in e N-Oxid e (18). To a solution of pyridine
17 (143 mg, 0.450 mmol) in freshly distilled CH2Cl2 (1.5 mL)
cooled to -78 °C was added m-CPBA (184 mg of 50 wt %
reagent, 0.530 mmol) in a single portion. The reaction was
monitored by TLC and was judged to be complete after stirring
for 2 h at -78 °C. The reaction was neutralized at -78 °C
with aqueous NaHCO3. After being warmed to room temper-
ature, the aqueous layer was separated and extracted with
CH2Cl2 (3 × 5 mL). The combined organic extracts were dried
(Na2SO4), and the solvent was removed with a rotary evapora-
tor. Flash chromatography (15:85 methanol/ethyl acetate) of
the crude material provided 151 mg (100%) of pyridine N-oxide
18. 1H NMR (400 MHz): δ -0.04 (s, 3), -0.01 (s, 3), 0.83 (s,
9), 1.46-1.52 (m, 2), 2.42 (s, 3), 2.56-2.62 (m, 2), 3.76 (s, 3),
4.11 (dd, 1, J ) 5.4, 11), 4.99 (d, 1, J ) 10.4), 5.13 (d, 1, J )
17.1), 5.70-5.78 (m, 1), 6.55 (d, 1, J ) 5.7), 8.04 (d, 1, J )
5.7). 13C NMR (100 MHz): δ -5.12, -4.61, 13.75, 18.01, 21.65,
25.56, 36.27, 55.64, 72.92, 104.82, 114.10, 127.37, 137.15,
140.54, 148.53, 155.33. Anal. Calcd for C18H31NO3Si: C,
64.05; H, 9.26; N, 4.15. Found: C, 64.03; H, 9.10; N, 4.10.
3-[3-(ter t-Bu tyld im eth ylsiloxy)-4-p en ten yl]-4-m eth oxy-
2-(p h en ylsu lfon yl)m eth ylp yr id in e N-Oxid e (19). To a
solution of pyridine N-oxide 18 (5.10 g, 15.0 mmol) in freshly
distilled CH2Cl2 (50 mL) was added p-toluenesulfonyl chloride
(4.38 g, 23.0 mmol). The resulting solution was cooled to -50
°C, and triethylamine (3.17 mL, 23.0 mmol) was added
dropwise over 75 min using a syringe pump. Over the course
of the addition, the reaction mixture became orange and
cloudy. The mixture was allowed to stir overnight, warming
to room temperature, and was then partitioned between
aqueous NH4Cl and CH2Cl2. The aqueous layer was extracted
with CH2Cl2 (3 × 50 mL), and the combined organic extracts
were dried (Na2SO4). The solvent was removed with a rotary
evaporator leaving a bright red oil, which was passed through
a plug of SiO2 (2.5:97.5 methanol/CHCl3). After evaporation
of the volatiles, the collected red oil was diluted in reagent-
grade DMF (30 mL). Sodium benzenesulfinate (2.46 g, 15.0
mmol) was added in a single portion, and the resulting bright
orange mixture was stirred at room temperature for 18 h and
1H NMR (500 MHz): major rotamer δ 2.40 (s, 3), 3.17-3.22
(m, 2), 3.38 (s, 3), 4.56 (dd, 1, J ) 5.3, 5.7), 4.84 (d, 1, J )
10.0), 4.95 (d, 1, J ) 17.0), 5.13-5.36 (m, 1), 6.50 (d, 1, J )
5.7), 7.30-7.62 (m, 5), 8.23 (d, 1, J ) 5.7); minor rotamer δ
2.78 (s, 3), 2.80-2.99 (m, 2), 3.33 (s, 3), 4.90 (d, 1, J ) 10.4),
5.03 (d, 1, J ) 17.0), 5.15 (dd, 1, J ) 4.3, 6.0), 5.39-5.56 (m,
1), 6.29 (d, 1, J ) 5.7), 7.30-7.62 (m, 5), 8.19(d, 1, J ) 5.7).
13C NMR (125 MHz): mixture of rotamers δ 23.45, 24.58,
29.79, 31.44, 54.76, 55.23, 60.52, 67.42, 103.32, 103.35, 104.94,
104.96, 114.42, 115.09, 117.80, 128.19, 128.62, 128.66, 128.93,
133.06, 133.24, 133.45, 138.32, 138.78, 150.29, 150.40, 159.82,
160.56, 164.05, 164.68. Anal. Calcd for C17H18NO3S: C, 64.33;
H, 6.03; N, 4.40. Found: C, 64.14; H, 5.99; N, 4.70.
4-Meth oxy-2-m eth yl-3-(3-bu ten yl)p yr id in e (14). Mer-
cury (16.92 g) was placed in a 100-mL flask equipped with a
magnetic stirring bar, and small pieces of Na (1.08 g, 47.0
mmol) that had been rinsed in hexanes were added one at a
time. The initial reaction was exothermic, creating flame and
smoke within the flask. As the amalgam was formed, however,
it was more sluggish in its reaction with the added Na, and a
heat gun was used to cause the last pieces of Na to react. The
freshly prepared 6% amalgam was cooled under N2, and Na2-
HPO4 (8.91 g, 63.0 mmol) was added in a single portion.
Sulfone 13 (5.00 g, 15.7 mmol) in methanol (52 mL) was then
added dropwise with a cannula at room temperature. The
resulting cloudy yellow solution was stirred for 2.5 h and was
then partitioned between water and CH2Cl2. The aqueous
layer was extracted with CH2Cl2 (3 × 50 mL), and the
combined organic extracts were dried (Na2SO4). The solvent
was removed with a rotary evaporator, and the remaining
residue was chromatographed on silica gel (1:99 methanol/
CHCl3) to afford 2.60 g (94%) of 14 as a pale yellow oil. 1H
NMR (400 MHz): δ 2.19-2.24 (m, 2), 2.50 (s, 3), 2.69 (t, 2, J
) 7.7), 3.83 (s, 3), 4.96 (d, 1, J ) 10.9), 5.03 (d, 1, J ) 17.1),
5.83-5.90 (m, 1), 6.63 (d, 1, J ) 5.7), 8.23 (d, 1, J ) 5.7). 13C
NMR (100 MHz): δ 22.05, 25.19, 32.80, 55.24, 104.06, 114.73,
123.68, 138.17, 147.80, 157.80, 160.18. Anal. Calcd for C11H15
-
NO: C, 74.54; H, 8.53; N, 7.90. Found: C, 73.94; H, 8.49; N,
7.91.
4-Met h oxy-2-m et h yl-3-(3-oxop r op yl)p yr id in e (15).
A
solution of compound 14 (1.23 g, 6.90 mmol) in 75:25 water/
THF (35 mL) was cooled to 0 °C, and OsO4 (1.75 mL of a 0.039
M solution in THF, 0.690 mmol) was added, followed im-
mediately by NaIO4 (3.69 g, 17.2 mmol). A cloudy suspension
formed and was stirred for 7 h, with warming to room
temperature. The mixture was partitioned between ethyl
acetate and water, and the aqueous layer was extracted with
ethyl acetate (3 × 30 mL). The combined organic extracts were
dried (Na2SO4), and the solvent was removed with a rotary
evaporator. The crude residue (1.09 g, 89%) was carried on
without purification. 1H NMR (400 MHz): δ 2.51 (s, 3), 2.61
(t, 2, J ) 8.1), 2.94 (t, 2, J ) 8.1), 3.83 (s, 3), 6.64 (d, 1, J )
5.7), 8.27 (d, 1, J ) 5.7), 9.81 (t, 1, J ) 1.5). 13C NMR (100
MHz): δ 18.47, 21.89, 42.54, 55.19, 104.04, 122.02, 148.26,
156.97, 163.37, 201.56.
3-(3-H yd r oxy-4-p en t en yl)-4-m et h oxy-2-m et h ylp yr i-
d in e (16). A solution of aldehyde 15 (2.81 g, 15.6 mmol) in
freshly distilled THF (150 mL), cooled to -50 °C, was treated
with vinylmagnesium bromide (15.6 mL of a 1.5 M solution
in THF, 23.5 mmol). The resulting mixture was allowed to
warm to room temperature as it stirred for 4.5 h. The reaction

Total Synthesis of Petrosins C and D
J . Org. Chem., Vol. 63, No. 15, 1998 5023
was then partitioned between water and ether. The aqueous
layer was extracted with ether (3 × 30 mL), and the combined
organic extracts were dried (Na2SO4). The volatiles were
removed with a rotary evaporator, and the remaining DMF
was removed under high vaccuum (30 min). The remaining
oil was chromatographed on silica gel (65:35 ethyl acetate/
hexane) to provide 3.49 g (50% from pyridine N-oxide 18) of
sulfone 19 as a pale yellow oil. 1H NMR (400 MHz): δ 0.02
(s, 3), 0.05 (s, 3), 0.89 (s, 9), 1.51-1.65 (m, 2), 2.57-2.74 (m,
2), 3.78 (s, 3), 4.15-4.19 (m, 1), 4.55 (s, 2), 5.03 (d, 1, J ) 10.4),
5.17 (d, 1, J ) 17.1), 5.74-5.82 (m, 1), 6.62 (d, 1, J ) 5.6),
7.41 (t, 2, J ) 7.9), 7.55 (t, 1, J ) 7.5), 7.67 (d, 2, J ) 7.4), 8.11
(d, 1, J ) 5.6). 13C NMR (100 MHz): δ -4.99, -4.64, 18.07,
21.03, 25.73, 36.67, 55.30, 61.45, 73.10, 105.58, 113.97, 128.01,
128.30, 128.69, 133.43, 138.97, 140.78, 147.27, 148.23, 164.01.
Anal. Calcd for C24H35NO4SSi: C, 62.43; H, 7.64; N, 3.03.
Found: C, 62.57; H, 7.57; N, 2.78.
3-(3-Acetoxy-4-pen ten yl)-4-m eth oxy-2-[(ph en ylsu lfon yl)-
m eth yl]p yr id in e (22) (Sch em e 3). A solution of allylic
alcohol 16 (8.79 g, 42.2 mmol) in freshly distilled CH2Cl2 (140
mL) was treated with freshly distilled triethylamine (19.6 mL,
140 mmol), acetic anhydride (9.20 mL, 97.0 mmol), and a
catalytic amount of 4-(dimethylamino)pyridine. The resulting
mixture was stirred at room temperature for 6.5 h and was
then partitioned between aqueous NH4Cl and CH2Cl2. The
aqueous layer was extracted with CH2Cl2 (3 × 80 mL), and
the combined organic extracts were dried (Na2SO4). Removal
of the solvent with a rotary evaporator provided a crude orange
oil that was chromatographed on silica gel (5:95 methanol/
CHCl3), providing 9.94 g (95%) of allylic acetate 20 as a pale
yellow oil. 1H NMR (400 MHz): δ 1.71-1.77 (m, 2), 2.02 (s,
3), 2.43 (s, 3), 3.77 (s, 3), 5.14 (d, 1, J ) 11.6), 5.20-5.24 (m,
2), 5.72-5.78 (m, 1), 6.57 (d, 1, J ) 5.7), 8.17 (d, 1, J ) 5.7).
13C NMR (100 MHz): δ 21.03, 21.15, 21.78, 32.73, 55.15, 74.35,
103.90, 116.65, 123.10, 136.05, 147.95, 156.99, 163.35, 170.14.
To a solution of allylic acetate 20 (890 mg, 3.60 mmol) in
freshly distilled CH2Cl2 (12 mL) was added m-CPBA (1.87 g
of 50 wt % reagent, 5.42 mmol) in a single portion. The
resulting white solution was stirred at room temperature for
3 h and was then partitioned between CH2Cl2 and saturated
NaHCO3. The aqueous layer was extracted with CH2Cl2 until
TLC analysis showed no product to be present in the aqueous
extracts. The combined organic extracts were dried (Na2SO4),
and the solvent was removed with a rotary evaporator. The
remaining residue was chromatographed on silica gel (2:98
methanol/CHCl3) to afford 917 mg (97%) of pyridine N-oxide
21 as a pale yellow oil. 1H NMR (400 MHz): δ 1.70-1.81 (m,
2), 2.09 (s, 3), 2.52 (s, 3), 2.66-2.70 (m, 2), 3.85 (s, 3), 5.22 (d,
1, J ) 10.6), 5.26-5.30 (m, 2), 5.76-5.81 (m, 1), 6.64 (d, 1, J
) 7.3), 8.17 (d, 1, J ) 7.3). 13C NMR (100 MHz): δ 13.77,
20.90, 21.72, 32.53, 55.70, 73.78, 104.91, 116.92, 126.23,
135.54, 137.42, 148.46, 155.20, 169.90.
To a solution of pyridine N-oxide 21 (7.25 g, 27.0 mmol) in
freshly distilled CH2Cl2 (90 mL) was added p-toluenesulfonyl
chloride (7.72 g, 41.0 mmol). The resulting solution was cooled
to -50 °C, and triethylamine (5.74 mL, 41.0 mmol) was added
dropwise over 60 min with a syringe pump. Over the course
of the addition, the reaction mixture became orange and
cloudy. The mixture was allowed to stir for 5 h, warmed to
room temperature, and partitioned between aqueous NH4Cl
and CH2Cl2. The aqueous layer was extracted with CH2Cl2
(3 × 30 mL), and the combined organic extracts were dried
(Na2SO4). The solvent was removed with a rotary evaporator,
leaving a bright red oil that was (without further purification)
diluted in reagent-grade DMF (54 mL). Sodium thiophenoxide
(4.65 g, 35.1 mmol) was added in a single portion, and the
resulting bright orange mixture was stirred at room temper-
ature for 12 h and was then partitioned between water and
ether. The aqueous layer was extracted with ether (3 × 60
mL), and the combined organic extracts were dried (Na2SO4).
The volatiles were removed with a rotary evaporator, and the
residual DMF was removed under high vaccuum (30 min). The
remaining oil was chromatographed on silica gel (55:45 ethyl
acetate/hexane) to provide 5.43 g (57% from pyridine N-oxide
21) of sulfide 22 as a pale yellow oil. 1H NMR (400 MHz): δ
1.80-1.86 (m, 2), 2.01 (s, 3), 2.67 (m, 2,), 3.83 (s, 3), 4.26 (s,
2), 5.16 (d, 1, J ) 10.5), 5.23-5.27 (m, 2), 5.74-5.78 (m, 1),
6.65 (d, 1, J ) 5.6), 7.16-7.41 (m, 5), 8.29 (d, 1, J ) 5.6). 13C
NMR (100 MHz): δ 21.01, 21.09, 33.34, 38.85, 55.36, 74.34,
104.93, 116.73, 124.24, 126.33, 128.73, 129.06, 136.00, 136.38,
148.52, 155.45, 163.90, 170.16. Anal. Calcd for C20H23NO3S:
C, 67.19; H, 6.48; N, 3.92. Found: C, 67.11; H, 6.62; N, 4.00.
Su lfon e 23. Before carrying out this reaction, both allylic
acetate 22 and sulfone 19 were separately azeotroped with
benzene and placed under high vacuum to ensure dryness.
Sulfone 19 (1.78 g, 3.80 mmol) was dissolved in freshly distilled
THF (3 mL) and cooled to -78 °C. In a separate pear-shaped
flask was dissolved NaHMDS (892 mg of an 84 wt % reagent,
4.09 mmol) in THF (3 mL). The resulting yellow solution was
added dropwise with a Teflon cannula to the cooled sulfone
solution. An additional portion of THF (500 µL) was passed
through the cannula as a rinse. The resulting yellow/orange
anionic solution was stirred under argon at -78 °C for 70 min
and was then warmed to 0 °C. While the sulfone was warming
to 0 °C, in a separate flask were dissolved Pd2(dba)3‚CHCl3
(136 mg, 3.7 mol %) and 1,2-bis(diphenylphosphino)ethane
(157 mg, 11.1 mol %) in THF (1 mL). The resulting dark
purple mixture was stirred at room temperature for 10 min
to give the active catalyst as a homogeneous yellow/orange
solution. Allylic acetate 22 (1.25 g, 3.55 mmol) was dissolved
in THF (3 mL) and was added dropwise with a Teflon cannula
to the active catalyst solution. The resulting red/orange
mixture was immediately added with a cannula to the anionic
solution at 0 °C. An additional portion of THF (500 µL) was
passed through the cannula as a rinse. The ice bath was
removed and replaced with a heating mantle. Under a steady
stream of argon, a reflux condenser was attached, and the
mixture was heated at reflux for 4 h. After cooling, the
mixture was partitioned between ethyl acetate and saturated
NH4Cl. The aqueous layer was extracted with ethyl acetate
(2 × 10 mL), and the combined organic extracts were dried
(Na2SO4). Evaporation of the solvent provided an impure red
oil that was purified by flash chromatography on silica gel (40:
60 hexanes/ethyl acetate) to afford 2.03 g (76%) of 23 as a
mixture of diastereomers. 1H NMR (d8-toluene, 100 °C, 400
MHz): δ 0.09 (s, 1.5), 0.11 (s, 1.5), 0.13 (s, 1.5), 0.17 (s, 1.5),
0.99 (s, 4.5), 1.01 (s, 4.5), 1.70-1.89 (m, 2), 1.91-1.95 (m, 2),
2.59 (dt, 2, J ) 2.2, 5.6), 2.83-2.88 (m, 1.5), 3.09-3.31 (m,
1.5), 3.20-3.30 (m, 2), 3.27 (s, 3), 3.31 (s, 3), 4.15 (s, 2), 4.25
(t, 1, J ) 5.7), 4.77 (dt, 1, J ) 4.1, 5.9), 5.04 (dt, 1, J ) 1.5,
10.9), 5.17-5.28 (m, 1), 5.44-5.50 (m, 1), 5.86-5.95 (m, 1),
6.14 (d, 1, J ) 5.6), 6.18 (d, 1, J ) 5.4), 6.90-7.12 (m, 6), 7.35
(d, 2, J ) 7.1), 7.66 (dt, 2, J ) 1.56, 7.0), 8.00 (d, 0.5, J ) 5.5),
8.02 (d, 0.5, J ) 5.5), 8.09 (d, 1, J ) 5.5). 13C NMR (100
MHz): δ -3.89, -3.72, -3.60, 19.04, 21.72, 21.91, 26.58, 26.75,
26.79, 26.85, 31.15, 31.21, 33.12, 33.66, 34.94, 38.44, 38.52,
40.11, 55.35, 55.43, 55.51, 70.08, 74.79, 105.59, 105.68, 106.09,
108.18, 114.49, 114.64, 126.71, 127.25, 127.31, 130.71, 130.99,
131.20, 133.20, 133.98, 137.22, 138.54, 140.43, 140.55, 142.45,
142.70, 148.57, 148.96, 153.59, 157.66, 164.73, 164.82. Anal.
Calcd for C42H54N2O5S2Si: C, 66.44; H, 7.17; N, 3.69. Found:
C, 66.04; H, 7.15; N, 3.54.
Allylic Alcoh ol 24. Sodium amalgam was prepared in a
100-mL flask equipped with a magnetic stirring bar from 726
mg of mercury and 44 mg (1.9 mmol) of Na (44 mg, 1.9 mmol)
as described previously in the preparation of compound 14.
The freshly prepared 6% amalgam was cooled under N2, and
Na2HPO4 (323 mg, 2.27 mmol) was added in a single portion.
Sulfone 23 (287 mg, 0.380 mmol) in methanol (2.0 mL) was
then added dropwise with a cannula at room temperature. The
resulting cloudy yellow solution was stirred for 2 h and was
then partitioned between water and CH2Cl2. The aqueous
layer was extracted with CH2Cl2 (3 × 5 mL), and the combined
organic extracts were dried (Na2SO4). The solvent was re-
moved with a rotary evaporator, and the remaining residue
was chromatographed on silica gel (70:30 ethyl acetate/
hexanes), affording 174 mg (66%) of the tert-butyldimethylsilyl
ether of alcohol 24 as a pale yellow oil. This compound is a
mixture of diastereomers, and many of the NMR resonances

5024 J . Org. Chem., Vol. 63, No. 15, 1998
Heathcock et al.
were doubled. Anal. Calcd for C36H50N2O3SSi: C, 69.86; H,
8.14; N, 4.52. Found: C, 69.86; H, 8.07; N, 4.79.
then warmed to room temperature. While the anion was
warming to room temperature, in a separate 15-mL two-
A cooled (0 °C) solution of the foregoing silyl ether (1.05 g,
1.50 mmol) in freshly distilled THF (2.0 mL) was treated with
tetra-n-butylammonium fluoride (7.5 mL of a 1 M solution in
THF, 7.5 mmol). The resulting mixture was allowed to stir
for 5.5 h, warming to room temperature, and was then
partitioned between aqueous NH4Cl and CH2Cl2. The aqueous
layer was extracted with CH2Cl2 (3 × 5 mL), and the combined
organic extracts were dried (Na2SO4). The solvent was re-
moved with a rotary evaporator, and the remaining oil was
chromatographed on silica gel (5:95 methanol/ethyl acetate).
Allylic alcohol 24 (756 mg, 100%) was obtained as a pale yellow
oil. 1H NMR (400 MHz): δ 1.67 (m, 2), 2.17 (m, 2), 2.34 (m,
2), 2.64-2.75 (m, 6), 3.19 (br s, 1), 3.79 (s, 3), 3.80 (s, 3), 4.09
(t, 1, J ) 5.8), 4.26 (s, 2), 5.08 (d, 1, J ) 10.4), 5.24 (d, 1, J )
17.2), 5.39-5,49 (m, 2), 5.85-5.93 (m, 1), 6.58 (d, 1, J ) 5.7),
6.61 (d, 1, J ) 5.7), 7.13-7.39 (m, 5), 8.30 (m, 2). 13C NMR
(100 MHz): δ 21.10, 25.51, 31.97, 32.48, 34.63, 36.52, 38.79,
55.23, 55.29, 72.18, 103.77, 104.92, 114.28, 123.45, 124.69,
126.24, 128.70, 129.60, 129.92, 130.38, 136.40, 141.02, 148.02,
148.17, 155.50, 160.13, 163.54, 163.96. Anal. Calcd for
necked flask equipped with a coldfinger condenser were
dissolved Pd2(dba)3‚CHCl3 (7.8 mg, 24 mol % of Pd(0)) and 1,2-
bis(diphenylphosphino)ethane (7.5 mg, 30 mol %) in THF (550
µL) to give a deep red homogeneous solution. After being
stirred for 5-10 min, the catalyst solution was diluted with
THF (3.40 mL) to give a 0.0038 M solution of Pd(0) catalyst.
At rt, the bright yellow anion (if the anion is orange, it should
be quenched with water and repurified) was diluted with THF
(2.4 mL) to give a 0.02 M solution, which was taken into a
5-mL gastight syringe. Several drops of the anion were added
to the red catalyst solution before it was immersed in a hot
(70 °C) oil bath. Within 5 min, the catalyst solution turned
orange, and the dropwise addition of the anion to the refluxing
catalyst solution was initiated. The addition was complete
after 2 h, and the reaction mixture was stirred at reflux until
TLC analysis of the mixture indicated that no further conver-
sion was occurring (usually 5 additional h). After being cooled
to room temperature, the reaction mixture was partitioned
between ethyl acetate and aqueous NaHCO3, the aqueous layer
was extracted with ethyl acetate (3 × 5 mL), and the combined
organic extracts were dried (Na2SO4). Evaporation of the
solvent provided an oil that was purified by flash chromatog-
raphy on silica gel (3:97 methanol/ethyl acetate; TLC solvent
was 3:97 methanol/CHCl3) to afford 17.8 mg (56%) of macro-
cyclic sulfone 27 as a coarse yellow solid. 1H NMR (400
MHz): δ 2.10-2.25 (m, 5), 2.37-2.77 (m, 7), 2.94-2.97 (m, 1),
3.06-3.10 (m, 1), 3.78 (s, 3), 3.83 (s, 3), 4.75 (dd, 1, J ) 4.8,
9.6), 5.12-5.17 (m, 1), 5.32-5.45 (m, 2), 5.54-5.61 (m, 1), 6.54
(d, 1, J ) 5.7), 6.66 (d, 1, J ) 5.5), 7.37 (t, 2, J ) 7.6), 7.45 (d,
2, J ) 7.2), 7.54 (t, 1, J ) 7.4), 8.18 (d, 1, J ) 5.7), 8.20 (d, 1,
J ) 5.5). 13C NMR (100 MHz): δ 25.45, 25.49, 30.62, 31.81,
32.25, 32.37, 35.45, 55.16, 55.31, 67.62, 103.89, 105.51, 123.52,
125.56, 127.85, 128.36, 128.39, 129.41, 131.16, 133.33, 133.48,
137.03, 147.99, 150.40, 160.36, 163.65, 164.31.
Bis-p yr id in e 28. Small strips of aluminum foil (99 mg,
3.7 mmol) were dipped into an aqueous 2% HgCl2 solution for
15 s. The strips were rinsed thoroughly with 95% ethanol
followed by ether and added to a cooled (0 °C), stirring solution
of sulfone 27 (191 mg, 0.370 mmol) in 10:1 THF/water (21 mL).
The mixture was stirred at 0 °C for 1.5 h and filtered through
a pad of Celite, and the solvent was removed. Purification of
the residue by flash chromatography on silica gel (3.5:96.5
methanol/ethyl acetate) provided 113 mg (81%) of symmetrical
macrocycle 28 as a white solid. 1H NMR (400 MHz): δ 2.27-
2.35 (m, 4), 2.41-2.57 (m, 4), 2.67-2.73 (m, 4), 2.80-2.87 (m,
4), 3.83 (s, 6), 5.34-5.45 (m, 2), 5.55-5.63 (m, 2), 6.62 (d, 2, J
) 5.6), 8.29 (d, 2, J ) 5.6). 13C NMR (100 MHz): δ 25.94,
31.08, 31.86, 34.40, 55.13, 103.82, 123.15, 129.62, 131.02,
147.91, 159.98, 163.70.
C
30H36N2O5S: C, 71.39; H, 7.19; N, 5.55. Found: C, 71.72; H,
6.95; N, 5.52.
Allylic P iva la te 25. To a solution of allylic alcohol 24 (1.22
g, 2.41 mmol) in freshly distilled CH2Cl2 (3.0 mL) was added
distilled triethylamine (1.70 mL, 12.1 mmol), trimethyl acetic
anhydride (2.44 mL, 12.1 mmol), and a catalytic amount of
4-(N,N-dimethylamino)pyridine. The resulting solution was
stirred at room temperature for 50 h and was then partitioned
between CH2Cl2 and saturated NH4Cl. The aqueous layer was
extracted with CH2Cl2 (3 × 12 mL), and the combined organic
extracts were dried (Na2SO4). Evaporation of the solvent
provided a yellow oil that was purified by flash chromatogra-
phy on silica gel (2:98 methanol/ethyl acetate) to afford 1.39 g
(98%) of 25 as a pale yellow oil. 1H NMR (400 MHz): δ 1.22
(s, 9), 1.75-1.79 (m, 2), 2.16-2.20 (m, 2), 2.33-2.38 (m, 2),
2.64 (dt, 4, J ) 5.8, 8.0), 2.88 (t, 2, J ) 8.3), 3.80 (s, 3), 3.82 (s,
3), 4.25 (s, 2), 5.15 (d, 1, J ) 10.6), 5.22-5.31 (m, 2), 5.48 (dd,
2, J ) 1.6, 5.2), 5.76-5.84 (m, 1), 6.59 (d, 1, J ) 5.7), 6.64 (d,
1, J ) 5.7), 7.13-7.40 (m, 5), 8.27 (d, 1, J ) 5.6), 8.28 (d, 1, J
) 5.7). 13C NMR (100 MHz): δ 20.97, 25.72, 27.22, 27.47,
32.24, 32.73, 33.80, 34.79, 38.90, 55.31, 55.39, 73.87, 103.93,
105.01, 116.20, 123.12, 124.83, 126.34, 128.81, 130.02, 130.06,
130.10, 136.39, 136.62, 148.27, 148.37, 155.57, 160.06, 163.73,
164.04, 177.63. Anal. Calcd for C35H44N2O4S: C, 71.39; H,
7.53; N, 4.75. Found: C, 71.11; H, 7.67; N, 4.72.
Su lfon e 26. A solution of sulfide 25 (1.09 g, 1.85 mmol) in
freshly distilled CH2Cl2 (9.2 mL) was treated with a single
portion of tetra-n-butylammonium peroxymonosulfate (5.23 g
of a 38 wt % solid, 5.55 mmol). The resulting viscous mixture
was stirred at room temperature for 24 h and was then
partitioned between CH2Cl2 and 1 N NaOH. The aqueous
layer was separated and extracted with CH2Cl2 (3 × 10 mL),
and the combined organic extracts were dried (Na2SO4).
Evaporation of the solvent provided a yellow oil that was
purified by flash chromatography on silica gel (2.5:97.5
methanol/ethyl acetate) to provide 903 mg (78%) of sulfone 26
as a pale yellow oil. 1H NMR (400 MHz): δ 1.21 (s, 9), 1.75
(m, 2), 2.10 (m, 2), 2.33 (m, 2), 2.62 (m, 2), 2.69-2.75 (m, 4),
3.79 (s, 3), 3.81 (s, 3), 4.55 (s, 2), 5.13 (d, 1, J ) 10.6), 5.21-
5.29 (m, 2), 5.43 (m, 2), 5.75-5.84 (m, 1), 6.59 (d, 1, J ) 5.6),
6.64 (d, 1, J ) 5.6), 7.43 (t, 2, J ) 7.8), 7.56 (t, 1, J ) 7.2), 7.67
(t, 2, J ) 7.4), 8.10 (d, 2, J ) 5.5), 8.25 (d, 1, J ) 5.6). 13C
NMR (100 MHz): δ 20.81, 25.56, 27.08, 31.73, 32.50, 33.64,
34.66, 38.77, 55.18, 55.36, 61.72, 73.73, 103.82, 105.67, 116.06,
122.92, 127.46, 128.37, 128.76, 129.51, 130.31, 133.49, 136.24,
138.94, 147.52, 148.21, 148.31, 159.86, 163.52, 164.08, 177.51.
Ma cr ocyclic Su lfon e 27. Before carrying out this reaction,
sulfone 26 was azeotroped with benzene and placed under high
vacuum to ensure dryness. Sulfone 26 (38.8 mg, 0.630 mmol)
was dissolved in freshly distilled THF (630 µL), cooled to -78
°C under argon, and treated with NaHMDS (72 µL of a 1 M
solution in THF, 0.66 mmol). A bright yellow solution resulted
and was stirred at -78 °C for approximately 30 min and was
Bis-p yr id in e 7. Raney nickel (20 mg of a 50% slurry in
water, 20 wt %) was washed several times with ether and
placed under N2. A solution of macrocyclic sulfone 28 (52 mg,
0.10 mmol) in reagent-grade methanol (300 µL) was added to
the catalyst with
a cannula. The flask was alternately
evacuated (aspirator) and purged with H2 three times, and the
mixture was stirred under a positive pressure of H2. After 20
h, the reaction mixture was partitioned between CH2Cl2 and
a 0.05 M solution of NaOH. The aqueous layer was extracted
with CH2Cl2 (3 × 5 mL), and the combined organic extracts
were dried (Na2SO4). Removal of the solvent and purification
of the remaining residue by flash chromatography on silica
gel (3:97 methanol/CHCl3) afforded 34 mg (65%) of 7 as a white
solid. 1H NMR (400 MHz): δ 1.51-1.55 (m, 12), 1.72-1.76
(m, 4), 2.60-2.62 (m, 4), 2.72-2.76 (m, 4), 3.83 (s, 6), 6.59 (d,
2, J ) 5.6), 8.27 (d, 2, J ) 5.6). 13C NMR (100 MHz): δ 25.25,
28.45, 28.48, 28.66, 29.39, 34.49, 55.20, 103.65, 124.01, 148.05,
160.89, 163.88.
(E)-3-[5-(ter t-Bu t yld im et h ylsiloxy)p en t -3-en -1-yl]-4-
m eth oxy-2-m eth ylp yr id in e (30). To a solution of the sul-
fone 12 (305 mg, 1.1 mmol) in dry THF (5 mL) was added
n-BuLi (460 µL, 1.1 mmol) at -78 °C. The solution was
allowed to warm to -50 °C over 0.5 h, before addition to the
allylic chloride (265 mg, 1.2 mmol) in THF (500 µL) at room

Total Synthesis of Petrosins C and D
J . Org. Chem., Vol. 63, No. 15, 1998 5025
temperature. The solution was stirred for 40 min and then
quenched with saturated NH4Cl (aq). Ether was added, and
the layers were separated, re-extracting the aqueous solution
twice with ether. The organic extracts were combined and
dried (Na2SO4). The solvent was removed under reduced
pressure to afford a brown oil that was purified on SiO2 (7 ×
3.5 cm) eluting with CH2Cl2/MeOH (100:0 then 99:1) to provide
compound 29 (444 mg, 0.96 mmol, 87%). NMR spectra were
complicated by the presence of two rotational isomers.
To a freshly prepared Na/Hg amalgam (50 g of 5 wt %) and
NaH2PO4 (14.4 g, 120 mmol) in MeOH (10 mL) was added a
solution of the sulfone 29 (4.43 g, 9.6 mmol) in MeOH (50 mL)
with ice cooling. When the addition was complete, the bath
was removed and the mixture stirred at room temperature for
6 h. The bulk of the solvent was removed under reduced
pressure, and the residue was partitioned between water and
CH2Cl2 and then decanted from the mercury metal. The layers
were separated, re-extracting the aqueous solution twice with
CH2Cl2. The organic extracts were combined and dried (Na2-
SO4). The solvent was removed under reduced pressure to
afford a yellow oil (2.6 g). The material was purified on SiO2
(9 × 4 cm), eluting with EtOAc/hexanes (1:1) to provide the
title compound 30 (2.87 g, 8.9 mmol, 93%) as a colorless oil.
1H NMR (400 MHz): δ 0.07 (s, 6), 0.91 (s, 9), 2.17-2.25 (m,
2), 2.50 (s, 3), 2.67-2.72 (m, 2), 3.82 (s, 3), 4.12 (dd, 2, J ) 1.3,
5.2), 5.57 (ddt, 1, J ) 10.0, 3.9, 6.6), 5.67-5.77 (m, 1), 6.63 (d,
1, J ) 5.7), 8.23 (d, 1, J ) 5.7). 13C NMR (100 MHz): δ -5.1,
18.4, 22.2, 25.5, 26.0, 31.3, 55.2, 63.9, 104.0, 123.7, 129.7, 130.4,
148.0, 157.2, 163.5. Anal. Calcd for C18H31NO2Si: C, 67.2;
H, 9.7; N, 4.4. Found: C, 67.0; H, 10.0; N, 4.2.
(E)-3-(5-Ch lor op en t-3-en -1-yl)-4-m eth oxy-2-m eth ylp y-
r id in e (31). To a solution of the silyl ether 30 (132 mg, 0.41
mmol) in THF (2 mL) was added 1 N HCl (2 mL) at room
temperature. After 0.25 h, aqueous Na2CO3 was added to
adjust the pH to about 10. CH2Cl2 was added, and the layers
were separated, re-extracting the aqueous solution twice with
CH2Cl2. The organic extracts were combined and dried (Na2-
SO4). The solvent was removed under reduced pressure to
afford a colorless oil. Purification by chromatography on SiO2
(1 × 2.5 cm) eluting with EtOAc/MeOH (19:1) afforded the
allylic alcohol (85 mg, 0.41 mmol, 100%) as a colorless oil that
solidified after prolonged standing in the refrigerator. 1H
NMR (400 MHz): δ 2.19 (dd, 2, J ) 6.9, 14.9), 2.48 (s, 3), 2.63-
6.70 (m, 2), 2.80-2.93 (br, 1), 3.81 (s, 3), 4.09 (dd, 2, J ) 5.5,
1.0), 5.65 (dt, 1, J ) 15.3, 5.5), 5.75 (dt, 1, J ) 15.3, 6.4), 6.62
(d, 1, J ) 5.7), 8.20 (d, 1, J ) 5.7). 13C NMR (100 MHz): δ
22.1, 25.5, 31.4, 55.4, 63.4, 104.2, 123.8, 130.0, 131.9, 147.9,
157.2, 163.7.
To an ice-cooled solution of the foregoing allylic alcohol (90
mg, 0.43 mmol), LiCl (42.5 mg, 1.0 mmol), and 2,6-lutidine
(120 µL, 1.0 mmol) in dry DMF (2 mL) was added MsCl (63
µL, 0.8 mmol). After 5 min, the cooling bath was removed and
the solution stirred at room temperature for 16.5 h. The
mixture was partitioned between aqueous Na2CO3 and ether,
and the organic layer was separated. The aqueous solution
was re-extracted twice with ether. The organic extracts were
combined, washed with three portions of water to remove any
residual DMF, and dried (Na2SO4). The solvent was removed
under reduced pressure to afford a yellow oil. The material
was purified on SiO2 (2.5 × 2.5 cm) eluting with EtOAc/
hexanes (1:1) to provide the title compound 31 as a colorless
oil (92 mg, 0.41 mmol, 95%). Due to the instability of the
allylic chloride, it was used without delay in the next reaction.
(E,E)-3-[5-(ter t-Bu tyld im eth ylsiloxy)p en t-3-en -1-yl]-2-
[6-(4-m eth oxy-2-m eth ylpyr idin -3-yl)h ex-3-en -1-yl]-4-m eth -
oxyp yr id in e (32). To a solution of the methylpyridine 30
(120 mg, 0.37 mmol) in THF (2 mL) was added n-BuLi (160
µL of 2.45 M, 0.39 mmol) dropwise at -78 °C. The resulting
solution was allowed to warm to -50 °C in the bath over 40
min and then treated with a solution of the allylic chloride 31
(60 mg, 0.27 mmol) in THF (1 mL). After 5 min at -50 °C,
the bath was removed and the solution allowed to stir at room
temperature for 10 min. Water was added, and the resulting
mixture was extracted with three portions of CH2Cl2. The
organic solutions were combined and dried (Na2SO4). The
solvent was removed under reduced pressure to afford a brown
oil that was purified on SiO2 (3 × 2.5 cm) eluting with EtOAc/
hexanes/MeOH (1:1:0, 1:0:0, 47:0:3) to afford the title com-
pound 32 as a pale yellow oil (116 mg, 0.23 mmol, 85% based
on 30). 1H NMR (400 MHz): δ 0.07 (s, 6), 0.90 (s, 9), 2.10-
2.25 (m, 4), 2.35-2.41 (m, 2), 2.49 (s, 3), 2.60-2.73 (m, 4),
2.75-2.82 (m, 2), 3.80 (s, 3), 3.81 (s, 3), 4.12 (dd, 2, J ) 1.2,
5.2), 5.45-5.60 (m, 3), 5.66-5.77 (m, 1), 6.61 (d, 2, J ) 5.7),
8.21 (d, 1, J ) 5.7), 8.29 (d, 1, J ) 5.7). 13C NMR (100 MHz):
δ -5.0, 18.6, 22.3, 25.2, 26.0, 26.2, 31.8, 32.1, 32.9, 35.1, 55.4,
55.4, 64.1, 104.0, 104.2, 123.6, 124.0, 129.8, 130.2, 130.3, 130.6,
148.0, 148.3, 157.4, 160.4, 163.7, 163.9.
(E,E)-3-[5-(ter t-Bu tyld im eth ylsiloxy)p en t-3-en -1-yl]-2-
[6-[4-m et h oxy-2-[(p h en ylsu lfa n yl)m et h yl]p yr id in -3-yl]-
h ex-3-en -1-yl]-4-m eth oxyp yr id in e (33). To a solution of the
compound 32 (40 mg, 0.078 mmol) in THF (1 mL) was added
n-BuLi (33 µL of 2.45 M, 0.081 mmol) dropwise at -78 °C.
The resulting orange solution was allowed to warm to -50 °C
over 20 min. The solution was recooled to -78 °C, and
PhSSPh (87 mg, 0.4 mmol) in THF (500 µL) was added in one
portion. The cooling bath was removed, and stirring was
continued at room temperature for 30 min. The pale yellow
solution was diluted with ether and washed with water. The
aqueous solution was extracted with an additional two portions
of ether. The organic extracts were combined and dried (Na2-
SO4). The solvent was removed under reduced pressure to
afford a yellow oil that was purified on SiO2 (6 × 1.5 cm)
eluting with EtOAc/hexanes (7:3 then 8:2) to provide the title
compound 33 (35 mg, 0.057 mmol, 73%) as a colorless oil. 1H
NMR (400 MHz): δ 0.07 (s, 6), 0.90 (s, 9), 2.15-2.25 (m, 4),
2.35-2.43 (m, 2), 2.61-2.73 (m, 4), 2.75-2.83 (m, 2), 3.83 (s,
3), 3.84 (s, 3), 4.12 (dd, 2, J ) 1.2, 5.2), 4.27 (s, 2), 5.50 (quintet,
2, J ) 2.7), 5.53-5.60 (m, 1), 5.67-5.75 (m, 1), 6.63 (d, 1, J )
5.7), 6.66 (d, 1, J ) 5.7), 7.18 (tt, 1, J ) 1.2, 7.3), 7.23-7.28
(m, 2), 7.39-7.43 (m, 2), 8.30 (d, 2, J ) 5.7). 13C NMR (100
MHz): δ -5.2, 18.4, 24.9, 25.6, 25.9, 31.7, 32.1, 32.7, 33.8, 38.8,
55.4, 55.7, 63.7, 104.3, 105.0, 124.4, 125.0, 126.5, 129.0, 129.8,
130.1, 130.2, 130.6, 136.7, 146.7, 148.5, 155.6, 159.2, 164.2,
165.0.
(E,E)-3-[5-(P iva loyloxy)pen t-3-en -1-yl]-2-[6-[4-m eth oxy-
2-(p h en ylsu lfa n yl)m et h ylp yr id in -3-yl]h ex-3-en -1-yl]-4-
m eth oxyp yr id in e (34). To an ice-cooled solution of the TBS
ether 33 (32 mg, 0.052 mmol) in THF (500 µL) was added a
solution of TBAF (70 µL of 1.0 M in THF, 0.07 mmol). The
solution was stirred at room temperature for 20 h and then
partitioned between H2O and CH2Cl2, and the layers were
separated. The aqueous solution was extracted with two
additional portions of CH2Cl2, and the organic layers were
combined and dried (Na2SO4). The solvent was removed under
reduced pressure to afford a yellow oil that was purified on
alumina (4 × 1.5 cm) eluting with EtOAc/methanol (1:0 then
98:2) to provide the alcohol (26 mg, 0.042 mmol, 80%) as a
colorless oil. 1H NMR (400 MHz): δ 2.17-2.26 (m, 5), 2.32-
2.38 (m, 2), 2.69 (apparent q, 4, J ) 7.5), 2.73-2.79 (m, 2),
3.84 (s, 3), 3.86 (s, 3), 4.11 (d, 2, J ) 5.0), 4.29 (s, 2), 5.46-
5.49 (m, 2), 5.66 (dt, 1, J ) 15.4, 5.5), 5.76 (dt, 1, J ) 15.4,
6.1), 6.63 (d, 1, J ) 5.7), 6.68 (d, 1, J ) 5.7), 7.19 (tt, 1, J )
1.2, 7.3), 7.23-7.30 (m, 2), 7.38-7.43 (m, 2), 8.29 (d,1, J )
5.7), 8.30 (d, 1, J ) 5.7). 13C NMR (100 MHz): δ 25.2, 25.8,
32.0, 32.2, 33.0, 35.0, 39.1, 55.5, 55.6, 63.7, 104.1, 105.2, 123.6,
124.9, 126.6, 129.0, 129.9, 130.0, 130.3, 130.6, 131.9, 136.7,
148.2, 148.5, 155.8, 160.2, 164.0, 164.3.
To a solution of the foregoing allylic alcohol (600 mg, 1.19
mmol) and Et3N (280 µL, 2.0 mmol) in CH2Cl2 (6 mL) was
added pivaloyl chloride (180 µL, 1.46 mmol), followed by DMAP
(15 mg, 0.12 mmol). The solution was stirred at room
temperature for 1.5 h and then diluted in CH2Cl2 and washed
with Na2CO3 (aq). The aqueous solution was extracted with
two additional portions of CH2Cl2, the organic extracts were
combined and dried (Na2SO4), and the solvent was removed
under reduced pressure to afford a yellow oil. Purification on
SiO2 (4.5 × 2.5 cm) eluting with EtOAc/hexanes (9:1 then 1:0)
provided the title compound 34 as a viscous oil (677 mg, 1.15
mmol, 97%). IR (film): 1726 cm-1
1.17 (s, 9), 2.15-2.25 (m, 4), 2.32-2.39 (m, 2), 2.67 (apparent
.
1H NMR (400 MHz): δ

5026 J . Org. Chem., Vol. 63, No. 15, 1998
Heathcock et al.
q, 4, J ) 7.5), 2.74-2.79 (m, 2), 3.79 (s, 3), 3.81 (s, 3), 4.25 (s,
2), 4.48 (dd, 2, J ) 1.0, 6.1), 5.45-5.57 (m, 3), 5.76 (dt, 1, J )
6.7, 15.4), 6.59 (d, 1, J ) 5.7), 6.63 (d, 1, J ) 5.7), 7.14 (tt, 1,
J ) 2.2, 7.2), 7.20-7.26 (m, 2), 7.36-7.41 (m, 2), 8.27 (d, 1, J
) 5.7), 8.27 (d, 1, J ) 5.7). 13C NMR (100 MHz): δ 24.9, 25.7,
27.2, 32.1, 32.3, 32.7, 34.9, 38.7, 39.0, 55.3, 55.4, 64.9, 104.0,
105.0, 123.1, 124.7, 124.8, 126.3, 128.8, 130.0, 130.0, 130.2,
134.6, 136.7, 148.3, 148.4, 155.6, 160.2, 163.8, 164.1, 178.3.
(E,E)-3-[5-(P iva loyloxy)pen t-3-en -1-yl]-2-[6-[4-m eth oxy-
2-(p h en ylsu lfon yl)m et h ylp yr id in -3-yl]h ex-3-en -1-yl]-4-
m eth oxyp yr id in e (35). A solution of the thioether 34 (677
mg, 1.15 mmol) and TBA-Oxone (2.8 g) in CH2Cl2 was stirred
at room temperature for 24 h. The mixture was diluted in
EtOAc and washed with Na2CO3 (aq), re-extracting the aque-
ous solution with two portions of EtOAc. The organic extracts
were combined and dried (Na2SO4), and the solvent was
removed under reduced pressure to afford a yellow oil.
Purification on SiO2 (4 × 2 cm) eluting with CH2Cl2/methanol
(99:1 then 19:1) provided the title compound 34 as a viscous
were separated, re-extracting the aqueous solution twice with
CH2Cl2. The organic extracts were combined and dried (Na2-
SO4). The solvent was removed under reduced pressure to
afford a brown oil (45 g). The material was divided into two
portions and purified on SiO2 (9 × 6.5 cm) eluting with EtOAc/
hexanes (4:6, 1:1, 1:0) to provide the title compound 36 (33.2
g, 72 mmol, 86%). 1H NMR reported for a mixture of rotational
isomers (400 MHz): δ 0.01 and 0.03 (s, 6), 0.86 and 0.84 (s,
9), 2.39 and 2.80 (s, 3), 2.99-3.32 (m, 2), 3.36 and 3.47 (s, 3),
3.97-4.05 and 4.12-4.21 (m, 2), 4.52 and 5.13 (dd, 1, J ) 5.1,
11.1 and 6.2, 10.6), 5.02-5.17 and 5.40-5.54 (m, 2), 6.32 and
6.55 (d, 1, J ) 5.7), 7.32-7.68 (m, 5), 8.23 and 8.26 (d, 1, J )
5.7). 13C NMR reported for a mixture of rotational isomers:
δ -5.12, -5.08, -5.07, 18.4, 23.6, 24.4, 24.6, 25.6, 26.0, 55.1,
55.5, 59.2, 59.4, 61.0, 67.6, 103.6, 105.2, 114.7, 124.9, 125.2,
128.4, 128.8, 128.9, 129.0, 132.9, 133.0, 133.5, 133.7, 139 2,
150.5, 150.6, 160.1, 160.8, 164.4, 165.0. Anal. Calcd for
C24H35NO4SiS: C, 62.4; H, 7.6; N, 3.0. Found: C, 62.3; H, 7.8;
N, 3.2.
oil (362 mg, 0.58 mmol, 51%). IR (film): 1725 cm-1
.
1H NMR
(Z)-3-[5-(ter t-Bu t yld im et h ylsiloxy)p en t -3-en -1-yl]-4-
m eth oxy-2-m eth ylp yr id in e (37). To a solution of sulfone
36 (4.0 g, 8.7 mmol) in MeOH (30 mL) was added NaH2PO4
(2.1 g, 15 mmol). Na/Hg amalgam (5%, a total of 12 g) was
added portionwise over 1 h. A small amount of water was
added to quench the excess amalgam, the bulk of the methanol
was removed under reduced pressure, and the residue was
partitioned between water and CH2Cl2 and then decanted from
the mercury metal. The layers were separated, re-extracting
the aqueous solution twice with CH2Cl2. The organic extracts
were combined and dried (Na2SO4). The solvent was removed
under reduced pressure to afford a yellow oil (2.9 g). The
material was purified on SiO2 (6 × 4.5 cm) eluting with EtOAc/
hexanes (3:7) to provide the title compound 37 (2.76 g, 8.6
mmol, 99%). 1H NMR (400 MHz): δ 0.0 (s, 6), 0.84 (s, 9), 2.17
(m, 2), 2.45 (s, 3), 2.61 (dd, 2, J ) 6.2, 8.1), 3.78 (s, 3), 4.07 (d,
2, J ) 4.6), 5.40-5.52 (m, 2), 6.58 (d, 1, J ) 5.7), 8.19 (d, 1, J
) 5.7). 13C NMR (100 MHz): δ -5.1, 18.4, 22.2, 25.7, 26.0,
26.7, 55.2, 59.2, 104.1, 123.5, 129.6, 130.5, 148.0, 157.3, 163.6.
Anal. Calcd for C18H31NO2Si: C, 67.2; H, 9.7; N, 4.4. Found:
C, 67.1; H, 9.9; N, 4.6.
(400 MHz): δ 1.18 (s, 9), 2.09-2.17 (m, 2), 2.23 (q, 2, J ) 7.3),
2.33-2.40 (m, 2), 2.65-2.80 (m, 6), 3.83 (s, 3), 3.84 (s, 3), 4.49
(dd, 2, J ) 0.9, 6.2), 4.58 (s, 2), 5.44-5.48 (m, 2), 5.55 (dt, 1, J
) 15.4, 6.2), 5.79 (dt, 1, J ) 15.4, 6.7), 6.63 (d, 1, J ) 5.7),
6.67 (d, 1, J ) 5.7), 7.46 (t, 2, J ) 7.5),7.60 (tt, 1, J ) 1.2, 7.5),
7.71 (dd, 2, J ) 1.2, 7.5), 8.13 (d, 1, J ) 5.7), 8.29 (d, 1, J )
5.7). 13C NMR (100 MHz): δ 24.9, 25.8, 27.3, 31.9, 32.1, 32.7,
34.9, 38.8, 55.3, 55.6, 61.9, 65.0, 104.0, 105.9, 123.2, 124.7,
127.7, 128.6, 129.0, 129.6, 130.7, 133.7, 134.7, 139.2, 147.7,
148.3, 148.5, 160.1, 163.8, 164.3, 178.4.
(4E,16E)-19-(Ben zen esu lfon yl)-12,24-d im et h oxy-9,21
d ia za tr icyclo[18.4.0.018,13]tetr a cosa -1(24),4,8(13),9,11,16,-
20,22-oct a en e ((E)-27) a n d (4E,16Z)-19-(Ben zen esu l-
fon yl)-12,24-d im et h oxy-9,21-d ia za t r icyclo[18.4.0.018,13
-
]tetr a cosa -1(24),4,8(13),9,11,16,20,22-octa en e ((Z)-27). To
a solution of the E,E-sulfone 35 (297 mg, 0.479 mmol) in THF
(40 mL) at -78 °C was added NaHMDS (560 µL of a 0.94 M
solution in THF, 0.527 mmol). The solution was allowed to
warm to room temperature. In a separate flask equipped with
a reflux condenser, a solution of Pd(dba)3‚CHCl3 (18.7 mg,
0.018 mmol) and dppe (18.2 mg, 0.0458 mmol) in THF (18 mL)
was warmed to gentle reflux, whereupon the solution changed
from a deep red to a pale orange color. The yellow solution of
the sulfone anion was added to the refluxing catalyst solution
over 2.5 h using a syringe pump. The resulting dark orange
mixture was then allowed to cool to room temperature, the
bulk of the THF was removed under reduced pressure, and
the residue was partitioned between CH2Cl2 and water. The
layers were separated, and the aqueous solution was re-
extracted twice with CH2Cl2. The organic solutions were
combined and dried (Na2SO4), and the solvent was removed
under reduced pressure to afford a viscous yellow oil. Puri-
fication on SiO2 (7 × 2.5 cm) eluting with EtOAc provided a
2.5:1 mixture of the title compounds (E)-27 and (Z)-27 as a
white solid (184 mg, 0.355 mmol, 74%). Data for (E)-27. 1H
NMR (400 MHz): δ 2.10-2.25 (m, 5), 2.37-2.77 (m, 7), 2.94-
2.97 (m, 1), 3.06-3.10 (m, 1), 3.78 (s, 3), 3.83 (s, 3), 4.75 (dd,
1, J ) 4.8, 9.6), 5.12-5.17 (m, 1), 5.32-5.45 (m, 2), 5.54-5.61
(m, 1), 6.54 (d, 1, J ) 5.7), 6.66 (d, 1, J ) 5.5), 7.37 (t, 2, J )
7.6), 7.45 (d, 2, J ) 7.2), 7.54 (t, 1, J ) 7.4), 8.18 (d, 1, J )
5.7), 8.20 (d, 1, J ) 5.5). 13C NMR (100 MHz): δ 25.4, 25.5,
30.6, 31.8, 32.2, 32.4, 35.5, 55.2, 55.3, 67.6, 103.9, 105.5, 123.5,
125.6, 127.8, 128.4, 128.4, 129.4, 131.2, 133.3, 133.5, 137.0,
148.0, 150.4, 160.4, 163.7, 164.3.
(Z)-3-(5-Hydr oxypen t-3-en -1-yl)-4-m eth oxy-2-m eth ylpy-
r id in e (38). To a solution of silyl ether 37 (11 g, 34.3 mmol)
in THF (75 mL) was added 1 N HCl (75 mL) at room
temperature. After 1 h, solid K2CO3 was added to adjust the
pH to about 10. The layers were separated, re-extracting the
aqueous solution twice with CH2Cl2. The organic extracts were
combined and dried (Na2SO4). The solvent was removed under
reduced pressure to afford a very pale yellow solid (7.1 g, 34.3
mmol, 100%). Crude 38 was routinely used without purifica-
tion in the next reaction. A sample of analytical purity was
prepared by chromatography on SiO2 eluting with EtOAc/
MeOH (1:0 then 19:1) followed by recrystallization (colorless
needles from EtOAc/petroleum ether. Mp: 75-77 °C. IR
(CHCl3): 3610 m, 3026 m, 2968 s, 1582 s, 1478 s, 1289 s cm-1
.
1H NMR (400 MHz): δ 2.17 (s, 1), 2.25-2.33 (m, 2), 2.53 (s,
3), 2.70 (dd, 2, J ) 7.5, 8.0), 3.88 (s, 3), 4.09 (d, 2, J ) 5.1),
5.58-5.68 (m, 2), 6.78 (d, 1, J ) 5.7), 8.26 (d, 1, J ) 5.7). 13C
NMR (100 MHz): δ 22.0, 25.7, 26.6, 55.4, 57.9, 104.2, 123.6,
130.1, 130.9, 147.8, 157.1, 163.8. Anal. Calcd for C12H17NO2:
C, 69.5; H, 8.3; N, 6.8. Found: C, 69.2; H, 8.0; N, 7.0.
(Z)-3-(5-Ch lor op en t-3-en -1-yl)-4-m eth oxy-2-m eth ylp y-
r id in e (39). To a mixture of allylic alcohol 38 (3.8 g, 18.4
mmol), 2,6-lutidine (3.1 mL, 27 mmol), and LiCl (1.1 g, 27
mmol) in dry DMF (54 mL) was added methanesulfonyl
chloride (2.1 mL, 27 mmol) dropwise with ice-cooling. When
the addition was complete, the bath was removed and the
mixture was stirred at room temperature for 4 h. The mixture
was partitioned between aqueous Na2CO3 and ether, and the
organic layer was separated. The aqueous solution was re-
extracted twice with ether. The organic extracts were com-
bined, washed with three portions of water to remove any
residual DMF, and dried (Na2SO4). The solvent was removed
under reduced pressure to afford a yellow oil. The material
was purified on SiO2 (8 × 4 cm) eluting with EtOAc/hexanes
(4:6 then 1:1) to provide the title compound 39 as a colorless
(Z)-3-[1-(Ben zen esu lfon yl)-5-(ter t-bu tyld im eth ylsiloxy-
)p en t-3-en -1-yl]-4-m eth oxy-2-m eth ylp yr id in e (36). To a
solution of sulfone 12 (23.2 g, 84 mmol) in THF (280 mL) at
-45 °C was added n-BuLi (35 mL of a 2.5 M solution in
hexane, 88.2 mmol) dropwise. After the addition was com-
plete, the bath was removed and the mixture allowed to warm
to 15 °C. (Z)-ClCH2CHdCHCH2OTBS8 (22 g, 100 mmol) was
added dropwise, and a slight exotherm was observed. The
reaction temperature was allowed to reach 29 °C. The brown
solution was stirred at room temperature for 50 min and then
poured into a saturated solution of NH4Cl (aq). The layers

Total Synthesis of Petrosins C and D
J . Org. Chem., Vol. 63, No. 15, 1998 5027
oil (2.8 g, 12.4 mmol, 67%). Due to the instability of allylic
chloride 39, it was used without delay in the next reaction.
(Z,Z)-3-[5-(ter t-Bu tyld im eth ylsiloxy)p en t-3-en -1-yl]-2-
[6-(4-m eth oxy-2-m eth yl-pyr idin -3-yl)h ex-3-en -1-yl]-4-m eth -
oxyp yr id in e (40). To a solution of methylpyridine 37 (4.8 g,
14.9 mmol) in THF (37 mL) was added n-BuLi (6.3 mL of 2.5
M, 15.6 mmol) dropwise at -78 °C. The resulting solution was
allowed to warm to -50 °C in the bath over 40 min and then
treated with a solution of allylic chloride 39 (2.8 g, 12.4 mmol)
in THF (10 mL). After 5 min at -50 °C, the bath was removed
and the solution allowed to stir at room temperature for 30
min. Water was added, and the resulting mixture was
extracted with three portions of CH2Cl2. The organic solutions
were combined and dried (Na2SO4). The solvent was removed
under reduced pressure to afford a yellow oil (7.0 g) that was
purified on SiO2 (12 × 4 cm) eluting with EtOAc/hexanes (1:1
then 1:0) to afford the title compound 40 as a colorless oil (5.4
g, 10.6 mmol, 85% based on 39). 1H NMR (400 MHz): δ 0.05
(s, 6), 0.88 (s, 9), 2.17-2.25 (m, 4), 2.38-2.47 (m, 2), 2.48 (s,
3), 2.62 (dd, 2, J ) 6.1, 8.2), 2.67 (dd, 2, J ) 7.7, 9.9), 2.76 (dd,
2, J ) 7.6, 9.7), 3.80 (s, 3), 3.83 (s, 3), 4.12 (d, 2, J ) 4.7),
5.40-5.55 (m, 4), 6.61 (d, 1, J ) 5.7), 6.63 (d, 1, J ) 5.7), 8.21
(d, 1, J ) 5.7), 8.30 (d, 1, J ) 5.7). 13C NMR (100 MHz): δ
-5.1, 18.4, 22.2, 25.3, 25.8, 26.0, 26.4, 27.3, 27.4, 34.8, 55.2,
55.3, 59.2, 103.9, 104.0, 123.2, 123.8, 129.5, 129.6, 130.5, 147.9,
148.3, 157.3, 160.2, 163.6, 163.7. Anal. Calcd for C30H46N2O3-
Si: C, 70.5; H, 9.1; N, 5.5. Found: C, 70.2; H, 9.2; N, 5.7.
(Z,Z)-3-[5-(ter t-Bu tyld im eth ylsiloxy)p en t-3-en -1-yl]-2-
[6-[[4-m et h oxy-2-(p h en ylsu lfa n yl)m et h yl]p yr id in -3-yl]-
h ex-3-en -1-yl]-4-m eth oxyp yr id in e (41). To a solution of
methyl pyridine 40 (4.1 g, 8.0 mmol) in THF (40 mL) was
added n-BuLi (5.7 mL of 1.56 M, 8.84 mmol) dropwise at -78
°C. The solution was allowed to warm to -20 °C over 40 min
then recooled to -50 °C. A solution of MgBr2‚OEt2 (10 mmol
in ether 10 mL) was added and the mixture stirred at between
-40 and -50 °C for 30 min. The solution was recooled to -78
°C, and PhSSPh (2.6 g, 12 mmol) in THF (10 mL) was added
over 10 s. The cooling bath was removed, and stirring was
continued at room temperature for 30 min. A saturated
aqueous solution of NH4Cl (aq) was added, and the layers were
separated, washing with 1 M NaOH (aq). The aqueous
solution was extracted with an additional portion of ether,
again washing with 1 M NaOH (aq). The organic extracts were
combined and dried (Na2SO4). The solvent was removed under
reduced pressure to afford a yellow oil (6.4 g) that was purified
on SiO2 (12 × 4 cm) eluting with EtOAc/hexanes (7:3, 9:1, 0:1)
to provide the title compound 41 as a colorless oil (3.6 g, 5.8
mmol, 72%) then EtOAc/MeOH (19:1) to recover starting
material 40 (660 mg, 1.3 mmol, 16%). 1H NMR (400 MHz): δ
0.02 (s, 6), 0.86 (s, 9), 2.15-2.29 (m, 4), 2.37-2.45 (m, 2), 2.64
(pair of overlapping dd, 4, J ) 8.0, 8.0), 2.74 (dd, 2, J ) 7.5,
8.3), 3.79 (s, 3), 3.81 (s, 3), 4.10 (d, 2, J ) 5.1), 4.27 (s, 2), 5.37-
5.55 (m, 4), 6.58 (d, 1, J ) 5.7), 6.62 (d, 1, J ) 5.7), 7.10-7.41
(m, 5), 8.26 (d, 1, J ) 5.7), 8.27 (d, 1, J ) 5.7). 13C NMR (100
MHz): δ -5.1, 18.4, 25.3, 25.8, 26.0, 27.0, 27.3, 27.4, 34.7, 39.0,
55.3, 55.4, 59.2, 104.0, 105.0, 123.3, 124.8, 126.3, 128.8, 129.4,
129.5, 129.8, 129.9, 130.5, 136.7, 148.2, 148.4, 155.6, 160.1,
163.8, 164.1.
128.8, 129.2, 129.8, 129.9, 130.1, 130.7, 136.5, 148.1, 148.3,
155.5, 160.0, 163.8, 164.2. Anal. Calcd for C30H36N2O3S: C,
71.4; H, 7.2; N, 5.5. Found: C, 71.5; H, 7.3; N, 5.5.
(Z,Z)-3-[5-(P iva loyloxy)p en t-3-en -1-yl]-2-[6-[4-m eth oxy-
2-[(p h en ylsu lfa n yl)m eth yl]p yr id in -3-yl]h ex-3-en -1-yl]-4-
m eth oxyp yr id in e (43). To a solution of allylic alcohol 42
(610 mg, 1.21 mmol) and Et3N (280 µL, 2.0 mmol) in CH2Cl2
(6 mL) was added pivaloyl chloride (220 µL, 1.8 mmol) followed
by DMAP (7 mg, 0.06 mmol). The solution was stirred at room
temperature for 2 h, diluted in CH2Cl2, and then washed with
water, re-extracting the aqueous layer twice with CH2Cl2. The
organic extracts were combined and dried (Na2SO4), and the
solvent was removed under reduced pressure to afford a yellow
oil. Purification on SiO2 (4.5 × 2.5 cm) eluting with EtOAc/
hexanes (9:1) provided the title compound 43 as a viscous oil
(678 mg, 1.15 mmol, 95%). 1H NMR (400 MHz): δ 1.18 (s, 9),
2.23-2.33 (m, 4), 2.38-2.47 (m, 2), 2.67 (dd, 4, J ) 6.2, 8.1),
2.77 (dd, 2, J ) 6.0, 8.2), 3.83 (s, 3), 3.86 (s, 3), 4.29 (s, 2), 4.52
(d, 2, J ) 5.8), 5.40-5.57 (m, 3), 5.61-5.70 (m, 1), 6.63 (d, 1,
J ) 5.7), 6.66 (d, 1, J ) 5.7), 7.15-7.28 (m, 3), 7.36-7.41 (m,
2), 8.29 (d, 1, J ) 5.7), 8.30 (d, 1, J ) 5.7). 13C NMR (100
MHz): δ 25.3, 25.8, 27.0, 27.2, 27.3, 34.8, 38.7, 39.0, 55.3, 55.4,
60.1, 104.0, 105.1, 123.0, 124.6, 124.8, 126.3, 128.8, 129.4,
129.9, 129.9, 133.6, 136.7, 148.4, 148.5, 155.6, 160.1, 163.8,
164.1, 178.4. Anal. Calcd for C35H44N2O4S: C, 71.4; H, 7.5;
N, 4.8. Found: C, 71.1; H, 7.5; N, 4.8.
(Z,Z)-3-[5-(P iva loyloxy)p en t-3-en -1-yl]-2-[6-[4-m eth oxy-
2-[(p h en ylsu lfon yl)m eth yl]p yr id in -3-yl]h ex-3-en -1-yl]-4-
m eth oxyp yr id in e (44). To an ice-cooled solution of thioether
43 (1.38 g, 2.35 mmol) in ethanol (26 mL) was added a solution
of ammonium molybdate (880 mg, 0.71 mmol) in H2O2 (1.75
mL of a 30% aqueous solution) dropwise. The yellow mixture
was stirred for 12 min and then partitioned between K2CO3
(aq) and CH2Cl2, extracting three times with CH2Cl2. The
organic solutions were combined and dried (Na2SO4), and the
solvent was removed under reduced pressure to afford a
viscous yellow oil. Purification on SiO2 (4.5 × 2.5 cm) eluting
with EtOAc/MeOH (99:1 then 98:2) provided the title com-
pound 44 as a viscous pale yellow oil (1.37 g, 2.21 mmol, 94%).
1H (400 MHz): δ 1.18 (s, 9), 2.23 (q, 2, J ) 7.9), 2.28 (q, 2, J
) 7.9), 2.37 (q, 2, J ) 7.9), 2.67 (dd, 2, J ) 6.1, 8.1), 2.70-2.77
(m, 4), 3.84 (s, 3), 3.86 (s, 3), 4.52 (dd, 2, J ) 1.2, 5.8), 4.61 (s,
2), 5.37-5.57 (m, 3), 5.64-5.72 (m, 1), 6.63 (d, 1, J ) 5.7), 6.66
(d, 1, J ) 5.7), 7.43-7.50 (m, 2),7.60 (tt, 1, J ) 1.3, 7.5), 7.70-
7.74 (m, 2), 8.13 (d, 1, J ) 5.7), 8.30 (d, 1, J ) 5.7). 13C NMR
(100 MHz): δ 25.2, 25.6, 26.5, 27.1, 27.2, 34.5, 38.6, 55.3, 55.5,
60.0, 61.9, 103.9, 105.8, 122.9, 124.5, 127.5, 128.4, 128.8, 130.0,
133.6, 139.1, 147.6, 148.3, 148.4, 159.9, 163.6, 164.2, 178.2.
Anal. Calcd for C35H44N2O6S: C, 67.7; H, 7.1; N, 4.5. Found:
C, 67.7; H, 7.3; N, 4.6.
(4Z,16Z)-19-(Ben zen esu lfon yl)-12,24-d im et h oxy-9,21-
d ia za tr icyclo[18.4.0.018,13]tetr a cosa -1(24),4,8(13),9,11,16,-
20,22-octa en e (45) a n d (4Z,16E)-19-(Ben zen esu lfon yl)-
12,24-d im eth oxy-9,21-d ia za tr icyclo[18.4.0.018,13]tetr a cosa -
1(24),4,8(13),9,11,16,20,22-octa en e (46). To a solution of
Z,Z-sulfone 44 (641 mg, 1.03 mmol) in THF (25 mL) at -78
°C was added NaHMDS (580 µL of a 1.97 M solution in THF,
1.14 mmol). The solution was allowed to warm to room
temperature. In a separate flask equipped with a reflux
condenser, a solution of Pd(dba)3‚CHCl3 (26.8 mg, 0.0258
mmol) and dppe (26.1 mg, 0.0655 mmol) in THF (26 mL) was
warmed to gentle reflux, whereupon the solution changed from
a deep red to a pale orange color. The yellow solution of the
sulfone anion was added to the refluxing catalyst solution over
1.5 h using a syringe pump. The resulting dark orange
mixture was then allowed to cool to room temperature, the
bulk of the THF was removed under reduced pressure, and
the residue was partitioned between CH2Cl2 and water. The
layers were separated, and the aqueous solution was re-
extracted twice with CH2Cl2. The organic solutions were
combined and dried (Na2SO4), and the solvent was removed
under reduced pressure to afford a viscous yellow oil. Puri-
fication on SiO2 (7 × 2.5 cm) eluting with EtOAc provided the
title compounds 45 and 46 as a white solid (387 mg, 0.75 mmol,
73%). The two isomers were inseparable by chromatography
(Z,Z)-3-(5-H yd r oxyp en t -3-en -1-yl)-2-[6-[4-m et h oxy-2-
[(p h en ylsu lfa n yl)m et h yl]p yr id in -3-yl]h ex-3-en -1-yl]-4-
m eth oxyp yr id in e (42). A mixture of silyl ether 41 (1.68 g,
2.72 mmol) in THF (5 mL) and 1 N HCl (5 mL) was stirred at
room temperature for 17 h. The pH of the reaction mixture
was carefully adjusted to about 10 with solid K2CO3. Extrac-
tion with three portions of CH2Cl2 followed by drying (Na2-
SO4) and removal of solvent under reduced pressure afforded
a yellow oil that was purified on alumina (6 × 2.5 cm) eluting
with EtOAc/MeOH (1:0, 99:1, 98:2) to provide the title com-
pound 42 (1.3 g, 2.56 mmol, 94%). 1H NMR (400 MHz): δ
2.18-2.40 (m, 7), 2.63 (dd, 2, J ) 7.7, 8.1), 2.67 (dd, 4, J )
7.4, 9.3), 3.84 (s, 3), 3.85 (s, 3), 4.07 (d, 2, J ) 5.9), 4.29 (s, 2),
5.40-5.65 (m, 4), 6.63 (d, 1, J ) 5.7), 6.66 (d, 1, J ) 5.7), 7.15-
7.28 (m, 3),7.36-7.40 (m, 2), 8.28 (d, 1, J ) 5.7), 8.29 (d, 1, J
) 5.7). 13C NMR (100 MHz): δ 25.3, 25.6, 26.9, 27.2, 27.2,
34.5, 38.8, 55.3, 55.4, 57.9, 104.0, 105.1, 123.3, 124.8, 126.3,

5028 J . Org. Chem., Vol. 63, No. 15, 1998
Heathcock et al.
on silica. A pure sample of 46 was obtained by HPLC:
Chirapak AD 25 cm × 2 cm column with a flow rate of 12 mL/
min monitoring with UV detection at 220 nm. Hexane:IPA
containing 1% diethylamine (85:15). 1H NMR (400 MHz): δ
2.0-2.35 (m, 6), 2.35-2.74 (m, 5), 2.88 (ddd, 1, J ) 7.0, 9.7,
13.9), 2.96 (ddd, 1, J ) 2.2, 9.7, 11.9), 3.24 (dt, 1, J ) 5.6, 12.0)
3.81 (s, 3), 3.83 (s, 3), 4.55 (dd, 1, J ) 2.4, 11.2), 5.15 (ddd, 1,
J ) 6.5, 7.6, 14.7), 5.44 (dt, 1, J ) 10.7, 6.1), 5.51-5.63 (m, 2),
6.60 (d, 1, J ) 5.9), 6.69 (d, 1, J ) 5.6), 7.42 (t, 2, J ) 8.2),
7.58 (m, 3), 8.24 (d, 1, J ) 5.6), 8.31 (d, 1, J ) 5.6). 13C NMR
(100 MHz): δ 24.1, 25.6, 28.1, 28.2, 31.7, 31.9, 36.4, 55.1, 55.4,
68.0, 104.1, 105.6, 123.3, 125.2, 128.4, 128.6, 129.3, 129.7,
133.5, 133.6, 137.4, 148.2, 148.3, 150.3, 160.0, 163.6, 163.9.
Anal. Calcd for C30H34N2O4S: C, 69.5; H, 6.6; N, 5.4. Found:
C, 69.3; H, 6.7; N, 5.4. APCI-MS m/z (rel intensity): 519 (MH+,
100). See direct cyclization for data (later) for 45.
(Z,Z)-3-[5-(ter t-Bu tyld im eth ylsiloxy)p en t-3-en -1-yl]-2-
[6-[4-m et h oxy-2-[(p h en ylsu lfon yl)m et h yl]p yr id in -3-yl]-
h ex-3-en -1-yl]-4-m et h oxyp yr id in e (47). To an ice-cooled
solution of thioether 41 (1.57 g, 2.54 mmol) in ethanol (26 mL)
was added a solution of ammonium molybdate (880 mg, 0.71
mmol) in H2O2 (1.75 mL of a 30% aqueous solution) dropwise.
The yellow mixture was stirred for 17 min and then partitioned
between (aq) and CH2Cl2, extracting three times with CH2-
Cl2. The organic solutions were combined and dried (Na2SO4),
and the solvent was removed under reduced pressure to afford
a viscous yellow oil. Purification on SiO2 (4 × 2.5 cm) eluting
with EtOAc/MeOH (99:1 then 98:2) provided the title com-
pound 47 as a colorless oil (1.58 g, 2.43 mmol, 96%). 1H (400
MHz): δ 0.02 (s, 6), 0.9 (s, 9), 2.21 (quintet, 4, J ) 7.5), 2.37
(q, 2, J ) 8.0), 2.65 (dd, 2, J ) 7.7, 8.1), 2.69-2.77 (m, 4), 3.83
(s, 6), 4.12 (d, 2, J ) 4.8), 4.61 (s, 2), 5.36-5.56 (m, 4), 6.62 (d,
1, J ) 5.7), 6.69 (d, 1, J ) 5.7), 7.47 (broad t, 2, J ) 7.8), 7.61
(tt, 1, J ) 1.4, 7.5), 7.73 (d, 2, J ) 7.5), 8.16 (d, 1, J ) 5.7),
8.29 (d, 1, J ) 5.7). 13C NMR (100 MHz): -5.1, 18.4, 25.3,
25.7, 26.0, 26.6, 27.2, 27.4, 34.6, 55.3, 55.5, 59.2, 62.0, 104.0,
105.9, 123.2, 127.6, 128.5, 128.9, 129.0, 129.5, 130.1, 130.5,
133.6, 139.1, 147.7, 148.3, 148.5, 160.0, 163.7, 164.3. Anal.
Calcd for C36H50N2O5SSi: C, 66.4; H, 7.7; N, 4.3. Found: C,
66.3; H, 7.8; N, 4.3. APCI-MS m/z (rel intensity): 651 (MH+,
100).
(Z,Z)-3-(5-H yd r oxyp en t -3-en -1-yl)-2-[6-[4-m et h oxy-2-
[(p h en ylsu lfon yl)m et h yl]p yr id in -3-yl]h ex-3-en -1-yl]-4-
m eth oxyp yr id in e (48). A mixture of silyl ether 47 (800 mg,
1.29 mmol) in THF (3 mL) and 1 N HCl (3 mL) was stirred at
room temperature for 8 h. The pH of the reaction mixture
was carefully adjusted to about 10 with solid K2CO3. Extrac-
tion with three portions of CH2Cl2 followed by drying (Na2-
SO4) and removal of solvent under reduced pressure afforded
a yellow oil which that purified on alumina (6 × 2.5 cm) eluting
with EtOAc/MeOH (99:1, 98:2) to provide the title compound
48 (610 mg, 1.21 mmol, 94%). 1H NMR (400 MHz): δ 2.13-
2.43 (m, 7), 2.61 (q, 4, J ) 8.6), 2.77 (t, 2, J ) 7.5), 3.83 (s, 6),
4.04 (d, 2, J ) 5.6), 4.62 (s, 2), 5.36-5.47 (m, 2), 5.50-5.64
(m, 2), 6.61 (d, 1, J ) 5.7), 6.67 (d, 1, J ) 5.6), 7.47 (t, 2, J )
7.7), 7.59 (t, 1, J ) 7.4), 7.70 (d, 2, J ) 8.0), 8.10 (d, 1, J )
5.7), 8.26 (d, 1, J ) 5.6). 13C NMR (100 MHz): δ 25.3, 25.5,
26.5, 27.1, 27.2, 34.4, 55.3, 55.5, 58.0, 61.8, 103.9, 105.8, 123.1,
127.6, 128.5, 128.7, 128.8, 129.6, 130.1, 131.2, 133.6, 138.9,
147.6, 148.2, 148.3, 159.9, 163.6, 164.4. APCI-MS m/z (rel
intensity): 537 (MH+, 100).
(4Z,16Z)-19-(Ben zen esu lfon yl)-12,24-d im et h oxy-9,21-
d ia za tr icyclo[18.4.0.018,13]tetr a cosa -1(24),4,8(13),9,11,16,-
20,22-octa en e (45). To a mixture of allylic alcohol 48 (1.2 g,
2.24 mmol) 2,6-lutidine (290 µL, 2.5 mmol), and LiCl (190 mg,
4.5 mmol) in dry DMF (10 mL) was added MsCl (200 µL, 2.5
mmol) dropwise with ice-cooling. When the addition was
complete, the bath was removed and the mixture was stirred
at room temperature for 2 h. The mixture was partitioned
between aqueous Na2CO3 and ether, and the organic layer was
separated. The aqueous solution was re-extracted twice with
ether. The organic extracts were combined, washed with three
portions of water to remove any residual DMF, and dried (Na2-
SO4). The solvent was removed under reduced pressure to
afford a yellow oil. The material was purified on alumina (6
× 4 cm) eluting with EtOAc/methanol (1:0 then 99:1) to provide
the title compound 49, which was contaminated with a small
amount of 2,6-lutidine, as a colorless oil (1.3 g, greater than
100% mass recovery). Due to the instability of the allylic
chloride, it was used without delay in the next reaction.
A solution of crude sulfone 49 (1.3 g) in THF (30 mL) was
added to a refluxing solution of NaHMDS (4 mL of 1.97 M in
THF) in THF (125 mL) over 2.5 h. The excess base was
quenched with H2O (1 mL), and the bulk of the THF was
removed under reduced pressure. The residue was partitioned
between CH2Cl2 and water. The layers were separated, and
the aqueous solution was re-extracted twice with CH2Cl2. The
organic solutions were combined and dried (Na2SO4), and the
solvent was removed under reduced pressure to afford a
viscous yellow oil. Purification on SiO2 (6 × 3.5 cm) eluting
with EtOAc provided the title compounds 45 as a white solid
(940 mg, 1.81 mmol, 81% over two steps). Mp: 186-187 °C
(white microcrystalline solid from EtOAc). 1H NMR (400
MHz): δ 1.95-2.61 (m, 10), 2.70-2.86 (m, 2), 2.91 (ddd, 1, J
) 3.4, 9.0, 11.8), 3.22 (dt, 1, J ) 7.4, 11.8), 3.81 (s, 3), 3.83 (s,
3), 4.49 (dd, 1, J ) 3.4, 11.3), 5.09-5.28 (m, 2), 5.39-5.57 (m,
2), 6.66 (d, 1, J ) 5.7), 6.70 (d, 1, J ) 5.6), 7.36 (t, 2, J )
7.6),7.50 (tt, 1, J ) 1.1, 7.6), 7.61 (dd, 2, J ) 1.2, 7.6), 8.30 (d,
1, J ) 5.7), 8.32 (d, 1, J ) 5.6). 13C NMR (100 MHz): d 24.7,
25.8, 26.1, 26.2, 27.7, 28.1, 36.1, 55.2, 55.4, 67.0, 104.1, 105.7,
122.9, 124.5, 128.2, 128.5, 128.7, 129.1, 129.7, 132.8, 133.5,
137.5, 148.3, 148.3, 150.1, 159.9, 163.8, 164.0. Anal. Calcd
for C30H34N2O4S: C, 69.5; H, 6.6; N, 5.4. Found: C, 69.6; H,
6.6; N, 5.4.
P yr id in e 50. A solution of symmetrical macrocycle 28 (28
mg, 0.07 mmol) in freshly distilled THF (740 µL) was cooled
to -78 °C and treated with n-butyllithium (90 µL of a 2.21 M
solution in THF, 0.20 mmol). A cloudy orange solution
resulted and was stirred for 1 h, warming to room tempera-
ture. At rt, the solution appeared homogeneous and darker
in color. Neat 1-bromo-3-chloropropane (34 µL, 0.35 mmol)
was added with a syringe, causing the solution to fade in color.
After being stirred at room temperature for 1 h, the volatiles
were removed with
a rotary evaporator, and the excess
1-bromo-3-chloropropane was removed under a static high
vacuum (15 min). The remaining residue was dissolved in
reagent-grade acetone (5 mL), and NaI (63 mg, 0.42 mmol)
was added. A reflux condenser was attached to the flask, and
the mixture was heated at reflux for 1.5 h to produce a crude
pyridinium salt. The solvent was removed with a rotary
evaporator, and the remaining salts were dissolved in distilled
THF (740 µL). After the mixture was cooled to -78 °C,
L-Selectride (246 µL of a 1 M solution in THF, 0.250 mmol)
was added. The mixture stirred, warming to room tempera-
ture over 2.5 h, and methanol (5 µL) was added cautiously to
quench any unreacted L-Selectride. The quenched reaction
mixture was diluted with water (740 µL), and NaBO3‚4H2O
(113 mg, 0.740 mmol) was added in small portions over 2 h.
An ice bath was used periodically to maintain a reaction
temperature of 25 °C. After all of the organoborane had been
oxidized, the reaction mixture was partitioned between ethyl
acetate and water. The aqueous layer was extracted with
ethyl acetate (3 × 5 mL), and the combined organic extracts
were washed with brine and dried (Na2SO4). Removal of the
solvent with a rotary evaporator and purification of the residue
by flash chromatography on silica gel (4:96 methanol/CHCl3)
afforded 15 mg (50%) of monoannulated pyridine 50. 1H NMR
(400 MHz): δ 1.43-1.48 (m, 2), 1.71-1.77 (m, 4), 1.92-1.99
(m, 4), 2.04-2.16 (m, 3), 2.34-2.86 (m, 8), 3.08 (dt, 1, J ) 5.3,
11.6), 3.21-3.24 (m, 2), 3.30 (ddd, 1, J ) 6.5, 12.8, 19.5), 3.85
(s, 3), 5.47-5.49 (m, 2), 5.51-5.58 (m, 2), 6.64 (d, 1, J ) 5.6),
8.34 (d, 1, J ) 5.6). 13C NMR (100 MHz): δ 18.08, 22.07, 22.21,
25.26, 25.67, 30.00, 31.51, 33.66, 34.10, 35.33, 36.51, 50.73,
51.30, 55.13, 103.74, 109.68, 123.29, 127.77, 130.03, 131.89,
131.99, 147.98, 159.43, 163.88, 164.32, 190.91.
19-(Ben zen esu lfon yl)-12,24-d im et h oxy-9,21-d ia za t r i-
cyclo[18.4.0.018,13]tetr a cosa -1(24),8(13),9,11,20,22-h exa en e
(52). A mixture of Z,Z-diene 45 (790 mg, 1.53 mmol), tosyl-
hydrazine (1.7 g, 9.1 mmol), and NaOAc (750 mg, 9.1 mmol)
in THF (9 mL) and water (9 mL) was heated at reflux for 14.5

Total Synthesis of Petrosins C and D
J . Org. Chem., Vol. 63, No. 15, 1998 5029
h. K2CO3 (aq) was added, and the mixture was extracted with
three portions of CH2Cl2. The organic solutions were combined
and dried (Na2SO4), and the solvent was removed under
reduced pressure to afford a white solid. Purification on SiO2
(4 × 2.5 cm) eluting with CH2Cl2/MeOH (1:0, 99:1 then 97.5:
2.5) provided the title compound 52 as a white solid (780 mg,
1.49 mmol, 97%). Mp: 205-205.5 °C (white microcrystalline
solid from CH2Cl2/ether). 1H NMR (500 MHz): δ 1.1-1.8 (m,
14), 2.25-2.35 (m, 1), 2.41 (dt, 1, J ) 3.8, 12.8), 2.5-2.7 (m,
5), 2.76 (dt, 1, J ) 5.4, 14.2), 3.80 (s, 3), 3.86 (s, 3), 4.80 (dd, 1,
J ) 3.1, 10.9), 6.57 (d, 1, J ) 5.7), 6.71 (d, 1, J ) 5.5), 7.40 (t,
2, J ) 7.7),7.53 (d, 2, J ) 7.7), 7.57 (t, 1, J ) 7.5), 8.21 (d, 1,
J ) 5.7), 8.27 (d, 1, J ) 5.5). 13C NMR (100 MHz): δ 24.0,
25.6, 27.6, 28.2, 28.8, 29.5, 29.6, 29.9, 34.5, 55.2, 55.4, 67.9,
103.8, 105.7, 123.8, 128.4, 128.5, 129.3, 133.5, 137.4, 148.0,
148.2, 150.6, 160.9, 163.7, 164.1. Anal. Calcd for
removed and the solution stirred at room temperature for 20
min. Brine was added, and the mixture was extracted with
three portions of CH2Cl2. The organic extracts were combined
and dried (Na2SO4), and the solvent was removed under
reduced pressure to afford a yellow oil. The starting macro-
cycle 54 (56 mg, 0.13 mmol, 18%) was recovered by chroma-
tography on SiO2 (3.5 × 2.5 cm) eluting with EtOAc/hexanes
(1:3, 1:1, 1:0). The mixture of products was separated by radial
chromatography on SiO2 eluting with EtOAc/hexanes (1:1) to
provide the following compounds (in order of elution):
Com p ou n d 58 (14 mg, 0.027 mmol, 4%) as a mixture of
diastereoisomers. Rf: 0.71 (EtOAc).
19-Allyl-10-br om o-12,24-d im eth oxy-9,21-d ia za tr icyclo-
[18.4.0.018,13]tetr a cosa -1(24),8(13),9,11,20,22-h exa en e (57)
(52 mg, 0.104 mmol, 14%). Rf: 0.63. 1H NMR (400 MHz): δ
1.2-1.7 (m, 16), 1.9-2.0 (m, 1), 2.36 (t, 2, J ) 7.0), 2.40-2.70
(m, 4), 2.80 (dt, 1, J ) 6.1, 13.5), 3.17 (quintet, 1, J ) 7.6),
3.80 (s, 3), 3.84 (s, 3), 4.83 (dd, 1, J ) 1.1, 10.1), 4.90 (dd, 1, J
) 1.1, 17.1), 5.57 (ddt, 1, J ) 10.1, 17.1, 7.1), 6.60 (d, 1, J )
5.5), 6.74 (s, 1), 8.38 (d, 1, J ) 5.5). 13C NMR (100 MHz): δ
24.6, 25.5, 27.7, 28.1, 29.1, 29.1, 29.2, 29.3, 29.5, 34.3, 34.5,
40.6, 41.7, 55.3, 55.8, 103.6, 107.8, 115.7, 124.0, 124.7, 137.3,
139.3, 148.4, 161.9, 163.0, 163.9, 165.1. FAB-MS m/z (rel
intensity): 503 (M+, 80), 501 (M+, 80).
Com p ou n d 56 (143 mg, 0.310 mmol, 42%). Mp: 84-86
°C (white powder from hexanes). 1H NMR (400 MHz): δ 1.2-
1.9 (m, 16), 2.2-2.3 (m, 2), 2.33-2.43 (m, 2), 2.55 (ddd, 2, J )
8.0, 8.0, 13.4), 2.65 (ddd, 2, J ) 5.1, 8.5, 13.5), 2.97-3.05 (m,
2), 3.82 (s, 6), 4.7-4.78 (m, 4), 5.40-5.53 (m, 2), 6.59 (d, 2, J
) 5.6), 8.33 (d, 2, J ) 5.6). 13C NMR (100 MHz): δ 24.2, 27.3,
28.1, 29.1, 34.5, 38.6, 41.1, 55.3, 103.5, 115.5, 124.3, 137.6,
148.3, 163.6, 163.8. Anal. Calcd for C30H42N2O2: C, 77.9; H,
9.1; N, 6.0. Found: C, 78.0; H, 9.2; N, 6.0.
Com p ou n d 55 (50 mg, 0.108 mmol, 15%). Mp: 99-102
°C (white powder from hexanes). 1H NMR (400 MHz): δ 1.15-
1.63 (m, 12), 1.63-1.75 (m, 2), 1.75-1.87 (m, 2), 2.38 (dd, 2, J
) 7.1, 13.5), 2.44 (dd, 2, J ) 7.1, 13.5), 2.49-2.58 (m, 2), 2.67-
2.77 (m, 2), 3.20 (quintet, 2, J ) 7.5), 3.82 (s, 6), 4.83 (dd, 2, J
) 2.2, 10.1), 4.93 (dd, 2, J ) 2.2, 17.1), 5.57 (ddt, 2, J ) 10.1,
17.1, 6.8), 6.58 (d, 2, J ) 5.6), 8.33 (d, 2, J ) 5.6). 13C NMR
(100 MHz): δ 25.6, 27.2, 28.8, 29.8, 34.1, 39.3, 39.7, 55.3, 103.5,
115.6, 125.0, 137.5, 148.3, 163.0, 163.7.
m eso-7,19-Bis(3-Hyd r oxyp r op -1-yl)-12,24-d im eth oxy-9,-
21-d ia za tr icyclo[18.4.0.018,13]tetr a cosa -1(24),8(13),9,11,20,-
22-h exa en e (62). To an ice-cooled solution of the diallyl
macrocycle 56 (170 mg, 0.368 mmol) in THF (7 mL) was added
9-BBN dimer (180 mg, 0.74 mmol). After 10 min, the bath
was removed and the solution was stirred at room temperature
for 19 h. NaOH (aq) (5 mL of 3 N) and H2O2 (5 mL of 30%
solution in water) were added with ice-cooling. The bath was
removed after 5 min and the mixture left for 2 h at room
temperature. The mixture was brought to reflux and then
stirred at room temperature for a further 2 h before being
extracted with three portions of CH2Cl2. The organic extracts
were combined and dried (Na2SO4), and the solvent was
removed under reduced pressure to afford a white solid that
was recrystallized three times from EtOAc to give the title
compound 62 as a white solid (110 mg, 0.221 mmol, 60%).
Further diol 62 (30 mg, 0.065, 18%) of lower purity was
obtained from purification of the residue on alumina (3 × 2.5
cm) eluting with EtOAc/MeOH (1:0, 99:1, 98:2, 96:4, 95:5). 1H
NMR (400 MHz): δ 1.09-1.21 (m, 2), 1.23-1.80 (m, 22), 2.22-
2.42 (br, 2), 2.55 (ddd, 2, J ) 7.9, 7.9, 13.4), 2.68 (ddd, 2, J )
5.1, 8.6, 13.4), 2.94 (broad septet, 2, J ) 7.5), 3.35-3.45 (m,
4), 3.83 (s, 6), 6.58 (d, 2, J ) 5.6), 8.29 (d, 2, J ) 5.6). 13C
NMR (100 MHz): δ 24.3, 27.1, 28.2, 29.0, 29.6, 30.8, 35.2, 40.4,
55.3, 62.9, 103.6, 124.5, 148.3, 163.9, 164.0.
C
30H38N2O4S: C, 68.9; H, 7.3; N, 5.4. Found: C, 69.0; H, 7.3;
N, 5.6.
19-Allyl-19-(b en zen esu lfon yl)-12,24-d im et h oxy-9,21-
d ia za tr icyclo[18.4.0.018,13]tetr a cosa -1(24),8(13),9,11,20,22-
h exa en e (53). To a solution of sulfone 52 (620 mg, 1.19 mmol)
in THF (6 mL) and 2,6-lutidine (3 mL) was added n-BuLi (1.6
mL of a 2.2 M solution in hexane, 3.5 mmol) dropwise at -78
°C. The orange slurry was stirred at -78 °C for 20 min. Allyl
iodide (500 µL, 5.47 mmol) was added, and the bath was
removed. After 30 min at room temperature, brine was added
and the mixture extracted with three portions of CH2Cl2. The
organic solutions were combined and dried (Na2SO4), and the
solvent was removed under reduced pressure to afford a yellow
solid. Purification on SiO2 (6 × 2.5 cm) eluting with CH2Cl2/
MeOH (99:1 then 98:2) provided the title compound 53 as a
white solid (630 mg, 1.12 mmol, 94%). Mp: 193-194 °C
(prisms from EtOAc). 1H NMR (500 MHz): δ 1.2-1.9 (m, 13),
2.22-2.35 (m, 2), 2.4-2.6 (m, 2), 2.73-2.9 (m, 2), 2.9-3.05 (m,
2), 3.1 (t, 1, J ) 11.6), 3.3-3.4 (m, 1), 3.62 (broad d, 1, J )
11.5), 3.79 (s, 3), 3.80 (s, 3), 4.97 (broad d, 1, J ) 10.2), 5.17
(broad d, 1, J ) 17.1), 5.50 (m, 1), 6.51 (d, 1, J ) 5.4), 6.56 (d,
1, J ) 5.7),7.17-7.25 (m, 4), 7.38 (tt, 1, J ) 1.5, 7.2), 7.77 (d,
1, J ) 5.4), 8.26 (d, 1, J ) 5.6). 13C NMR (100 MHz): δ 23.8,
25.9, 27.5, 27.8, 28.4, 28.7, 30.0, 31.1, 31.6, 32.5, 37.0, 55.3,
55.7, 78.2, 103.6, 105.2, 118.1, 124.4, 128.0, 129.5, 131.2, 132.8,
134.6, 137.1, 146.1, 148.1, 152.6, 160.9, 163.7, 165.5. Anal.
Calcd for C33H42N2O4S: C, 70.4; H, 7.5; N, 5.0. Found: C, 70.5;
H, 7.6; N, 4.9.
19-Allyl-12,24-dim eth oxy-9,21-diazatr icyclo[18.4.0.018,13]-
tetr a cosa -1(24),8(13),9,11,20,22-h exa en e (54). To a solu-
tion of sulfone 53 (207 mg, 0.37 mmol) in MeOH (3 mL) and
THF (3 mL) was added 5% Na/Hg amalgam (2 g) portionwise.
The mixture was stirred at room temperature for 12 h and
then decanted from the mercury metal, washing several times
with CH2Cl2. The solvent was removed under reduced pres-
sure to afford a white solid. Purification on SiO2 (2.5 × 2.5
cm) eluting with EtOAc provided the title compound 54 as a
white solid (142 mg, 0.34 mmol, 92%). Mp: 122-123 °C (white
prisms from ether/hexanes). 1H NMR (400 MHz): δ 1.2-1.8
(m, 15), 1.88-1.99 (m, 1), 2.34 (t, 2, J ) 7.0), 2.42-2.70 (m,
5), 2.79 (dt, 1, J ) 6.1, 13.5), 3.16 (quintet, 1, J ) 7.5), 3.77 (s,
3), 3.81 (s, 3), 4.78-4.92 (m, 2), 5.57 (ddt, 1, J ) 10.1, 17.1,
7.1), 6.51 (d, 1, J ) 5.7), 6.56 (d, 1, J ) 5.5), 8.21 (d, 1, J )
5.7), 8.35 (d, 1, J ) 5.5). 13C NMR (100 MHz): δ 24.4, 25.2,
27.4, 27.9, 28.8, 28.9, 29.1, 29.1, 29.4, 34.2, 34.3, 40.3, 41.4,
55.0, 55.0, 103.3, 103.6, 115.4, 123.9, 124.4, 137.0, 147.8, 148.1,
160.9, 162.8, 163.6, 163.6. Anal. Calcd for C27H38N2O2: C,
76.7; H, 9.1; N, 6.6. Found: C, 76.7; H, 9.2; N, 6.9.
(7R*,19R*)-7,19-Dia llyl-12,24-d im eth oxy-9,21-d ia za tr i-
cyclo[18.4.0.018,13]tetr a cosa -1(24),8(13),9,11,20,22-h exa en e
(55) a n d m eso-7,19-Dia llyl-12,24-d im et h oxy-9,21-d ia za -
tr icyclo[18.4.0.018,13]tetr acosa-1(24),8(13),9,11,20,22-h exaen e
(56). To a solution of the macrocycle 54 (314 mg, 0.744 mmol)
in ether (6 mL) containing TMEDA (120 µL, 0.8 mmol) was
added s-BuLi (580 µL of a 1.29 M solution in c-hexane, 0.744
mmol) dropwise at -78 °C. The resulting bright-orange
solution was stirred at -78 °C for 25 min. Allyl bromide (140
µL, 1.6 mmol) was added in one portion. The color discharged
rapidly, leaving a pale yellow solution. The cooling bath was
(7R*,19R*)-7,19-Bis-(3-h yd r oxyp r op -1-yl)-12,24-d im e-
th oxy-9,21-diazatr icyclo[18.4.0.018,13]tetr acosa-1(24),8(13),-
9,11,20,22-h exa en e (59). The same procedure used to pre-
pare diol 62 provided the racemic chiral diol 59 (85 mg, 0.171
mmol, 77%) as a white solid. 1H NMR (400 MHz): δ 1.15-
1.28 (m, 4), 1.30-1.81 (m, 20), 2.50-2.60 (m, 2), 2.60-2.75
(m, 4), 3.12 (quintet, 2, J ) 7.1), 3.43-3.55 (m, 4), 3.80 (s, 6),
6.57 (d, 2, J ) 5.6), 8.28 (d, 2, J ) 5.6). 13C NMR (100 MHz):

5030 J . Org. Chem., Vol. 63, No. 15, 1998
Heathcock et al.
25.6, 27.2, 28.8, 29.7, 30.5, 30.9, 34.9, 39.5, 55.3, 63.0, 103.5,
125.2, 148.3, 163.4, 163.8. Anal. Calcd for C30H46N2O4: C,
72.3; H, 9.3; N, 5.6. Found: C, 72.0; H, 9.6; N, 5.3.
(100 MHz): δ 20.1, 22.8, 23.3, 25.5, 26.7, 26.7, 28.2, 34.3, 42.4,
51.3, 57.1, 57.8, 71.3, 211.4.
P etr osin D (6). To a solution of the diketone 64 (15 mg,
0.034 mmol) in THF (1 mL) was added a freshly prepared
solution of LDA (240 µL of 0.37 M in THF/hexane, 0.088 mmol)
at -78 °C. After 5 min, the reaction solution was transferred
to an ice bath, and stirring was continued for 5 min during
which time a colorless precipitate formed. The mixture was
re-cooled to -78 °C, and MeI (8 µL, 0.130 mmol) was added.
After 10 min, the mixture was placed in an ice bath, as the
reaction proceeded the solid material dissolved. After 15 min,
the reaction was quenched by addition of a small amount of
water (ca. 100 µL). The solvent was removed under reduced
pressure, and the residue was taken up in MeOH (2 mL). K2-
CO3‚1.5H2O (0.2 mmol) was added and the mixture stirred at
room temperature for 14 h. The mixture was partitioned
between brine and CH2Cl2, and the layers were separated, re-
extracting the aqueous solution twice with CH2Cl2. The
organic solutions were combined and dried (Na2SO4). The
solvent was removed under reduced pressure to afford a buff
solid that was purified on alumina (6 × 1.5 cm) eluting with
CH2Cl2/MeOH (1:0, 99.75:0.25) to afford the petrosin D (5) as
a white solid (14 mg, 0.030 mmol, 88%). Mp: (sealed tube):
m eso-Dien ol Eth er (63). To a mixture of the diol 62 (110
mg, 0.221 mmol) and Et3N (280 µL, 2 mmol) in CH2Cl2 (4 mL)
at -78 °C was added methanesulfonyl chloride (60 µL, 0.8
mmol). The cooling bath was removed and the mixture stirred
at room temperature for 8 h. The solvent was removed under
reduced pressure to leave a yellow solid that was dissolved in
EtOH (8 mL). NaBH4 (250 mg, 6.6 mmol) was added portion-
wise and the resulting mixture stirred at room temperature
for 13 h. Brine was added and the mixture extracted with
three portions of CH2Cl2. The organic extracts were combined
and dried (Na2SO4) and the solvent was removed under
reduced pressure to afford a yellow solid that was purified on
alumina (6 × 2.5 cm) eluting with CH2Cl2/MeOH (1:0, 99.7:
0.3, 99.5:0.5, 99:1) followed by crystallization from MeOH to
provide 63 as a white solid (73 mg, 0.157 mmol, 71%). Mp:
170-172 °C. 1H NMR (400 MHz): δ 1.22-1.55 (m, 20), 1.70-
2.20 (m, 14), 2.28 (dt, 2, J ) 3.9, 11.1), 2.44-2.58 (m, 4), 2.76
(dd, 2, J ) 5.6, 10.7), 2.85 (broad d, 2, J ) 10.7), 3.48 (s, 6).
13C NMR (100 MHz): δ 21.0, 24.9, 25.4, 25.8, 26.2, 27.9, 29.7,
33.9, 53.0, 55.7, 57.5, 68.1, 117.7, 148.3. Anal. Calcd for
159-161 °C (colorless needles from MeOH). IR: 1711 cm-1
.
C
30H50N2O2: C, 76.5; H, 10.7; N, 6.0. Found: C, 76.5; H, 10.8;
N, 5.7.
Ch ir a l Dien ol Eth er (60). The same procedure used to
1H NMR (400 MHz): δ 0.97 (d, 6, J ) 6.5), 1.15-2.00 (m, 36),
2.44 (t, 2, J ) 9.2), 2.53 (septet, 2, J ) 6.2), 2.95 (broad d, 2,
J ) 11.4), 3.04 (dd, 2, J ) 5.5, 10.4). 13C NMR (100 MHz): δ
11.6, 20.1, 24.0, 24.2, 25.9, 26.7, 26.9, 29.5, 33.8, 44.4, 50.6,
57.0, 65.3, 71.9, 212.4.
prepare dienol ether 63 provided the racemic chiral dienol
ether 60 (40 mg, 0.085 mmol, 69%) as colorless prisms. Mp:
130-131 °C. 1H NMR (500 MHz): δ 0.7-1.07 (m, 2), 1.20-
1.55 (m, 20), 1.60-1.75 (m, 4), 1.75-1.97 (m, 4), 2.08-2.22
(m, 4), 2.25 (dt, 2, J ) 3.7, 11.1), 2.45-2.56 (m, 4), 2.76 (ddd,
2, J ) 1.0, 5.6, 10.7), 2.81-2.88 (m, 2), 3.47 (s, 6). 13C NMR
(100 MHz): δ 21.1, 24.7, 25.7, 27.0, 27.3, 28.4, 28.9, 30.1, 35.8,
53.0, 55.8, 57.4, 69.0, 117.8, 148.7.
P etr osin C (5). Petrosin C was prepared in the same way
as petrosin D (6). However, significant overmethylation
occurred in this case. Partial purification was carried out on
alumina (6 × 1.5 cm) eluting with CH2Cl2/MeOH (1:0, 99.75:
0.25) to afford the impure petrosin C as an oil. A pure sample
was obtained by radial chromatography on silica eluting with
EtOAc/MeOH (99.5:0.5) to provide petrosin C (5) as a white
solid. Mp: (sealed tube): 152-154 °C (colorless needles from
MeOH). 1H NMR (400 MHz): δ 0.96 (d, 6, J ) 6.5), 1.16-
2.00 (m, 36), 2.44 (t, 2, J ) 10.5), 2.53 (broad septet, 2, J )
6.1), 2.93 (broad d, 2, J ) 10.1), 3.04 (dd, 2, J ) 6.4, 11.4). 13C
NMR (100 MHz): δ 11.6, 20.1, 22.6, 23.2, 25.4, 26.6, 28.3, 34.4,
44.8, 51.2, 56.9, 65.8, 71.8, 77.4, 212.7.
Did em eth ylp etr osin D (64). To an ice-cooled solution of
the dienol ether 63 (73 mg, 0.157 mmol) in THF (10 mL) was
added HCl (aq) (10 mL of a 5 M solution) dropwise. After 20
min, the cooling bath was removed and stirring continued at
room temperature for 4 h. The reaction solution was cau-
tiously added to an excess of solid K2CO3, and the mixture was
partitioned between water and CH2Cl2. The layers were
separated, re-extracting the aqueous solution twice with CH2-
Cl2. The organic solutions were combined and dried (Na2SO4).
The solvent was removed under reduced pressure to afford a
buff solid that was purified on alumina (8 × 1.5 cm) eluting
with CH2Cl2/MeOH (1:0, 99.8:0.2, 9.7:0.3) to afford the title
compound 64 as a white solid (67 mg, 0.152 mmol, 97%). Mp:
171-172 °C (colorless plates from EtOAc/MeOH). IR: 1711
Ack n ow led gm en t. We thank the National Insti-
tutes of Health for support of this research (GM 46057).
R.C.D.B. thanks EPSRC for a NATO Postdoctoral
Fellowship.
cm-1
.
1H NMR (400 MHz): δ 1.15-1.65 (m, 22), 1.69-1.88
(m, 8), 1.93-2.02 (m, 4), 2.20-2.33 (m, 4), 2.44 (t, 2, J ) 8.6),
2.67 (dt, 2, J ) 5.4, 13.1), 2.95 (broad d, 2, J ) 11.7), 3.05-
3.12 (m, 2). 13C NMR (100 MHz): δ 20.1, 23.8, 24.3, 25.7, 26.6,
26.9, 29.4, 33.7, 42.0, 50.7, 57.3, 57.4, 71.3, 211.2.
Did em eth ylp etr osin C (61). The same procedure used
to prepare 64 provided the racemic chiral diketone 61 (27 mg,
0.061 mmol, 69%). 1H NMR (400 MHz): δ 1.17-2.03 (m, 34),
2.20-2.33 (m, 4), 2.42 (t, 2, J ) 10.2), 2.69 (dt, 2, J ) 6.3,
13.7), 2.95 (broad d, 2, J ) 11.0), 3.07-3.14 (m, 2). 13C NMR
Su p p or tin g In for m a tion Ava ila ble: Single-crystal X-ray
data for compound 60, 1H NMR and 13C NMR spectra of
compounds 5-7, 27, 28, 31-35, 41, 55, 57, 60-62, and 64
(45 pages). This material is contained in libraries on micro-
fiche, immediately follows this article in the microfilm version
of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
J O9801770