Complex biohopanoids synthesis: Efficient anchoring of ribosyl subunits onto a C30 hopane

Article abstract of DOI:10.1002/chem.200600659

Bacteriohopanoids represent a particularly important series of triterpenoids, widely distributed in bacteria. One of the common features of these pentacyclic hopanepolyols is the presence of an extended non-terpenoid and polyhydroxylated side chain attached to the triterpenic moiety through a C-C bond. The biological function of biohopanoids also has to be addressed when one considers the broad diversity in both structures and functionalities found in the side chain. Moreover, the stereochemistries of some biohopanoids are still unconfirmed, due to the lack of synthetic methods to prepare them. In this study we describe an efficient methodology for the formation of the C-C bond between the C₃₀-hopane component and C₅-polyhydroxylated carbohydrates through the use of a hopanyllithium intermediate, which has enabled us to synthesize several biohopanoid derivatives. We also report the first synthesis of hopanepentol bearing an additional hydroxy group at position C31.

Full text of DOI:10.1002/chem.200600659

FULL PAPER
DOI: 10.1002/chem.200600659
Complex Biohopanoids Synthesis: Efficient Anchoring of Ribosyl Subunits
onto a C30 Hopane
Weidong Pan,[a, c, d] Chao Sun,[a] Yongmin Zhang,[a] Guangyi Liang,[e] Pierre Sinaþ,*[a] and
StØphane P. Vincent*[b]
Abstract: Bacteriohopanoids represent
a particularly important series of triter-
penoids, widely distributed in bacteria.
One of the common features of these
pentacyclic hopanepolyols is the pres-
ence of an extended non-terpenoid and
polyhydroxylated side chain attached
in both structures and functionalities
found in the side chain. Moreover, the
stereochemistries of some biohopa-
noids are still unconfirmed, due to the
lack of synthetic methods to prepare
them. In this study we describe an effi-
cient methodology for the formation of
ꢀ
the C Cbond between the C 30-hopane
component and C5-polyhydroxylated
carbohydrates through the use of a ho-
panyllithium intermediate, which has
enabled us to synthesize several bioho-
panoid derivatives. We also report the
first synthesis of hopanepentol bearing
an additional hydroxy group at position
C31.
ꢀ
to the triterpenic moiety through a C
Keywords:
organocuprates
biosynthesis
· organolithium
·
·
Cbond. The biological function of bio-
hopanoids also has to be addressed
when one considers the broad diversity
steroids · terpenoids
Introduction
Biohopanoids are triterpenoids of the hopane series that are
widespread in a broad range of taxonomically different
strains of eubacteria.[1–9] In microorganisms the major bioho-
panoids are the C35 bacteriohopanepolyol derivatives, which
surprisingly possess an additional C5 non-terpenoid unit con-
[a] Dr. W. Pan, C. Sun, Dr. Y. Zhang, Prof. P. Sinaþ
Ecole Normale SupØrieure, DØpartement de Chimie
Institut de Chimie MolØculaire (FR 2769)
UMR 8642: CNRS-ENS-UPMC Paris 6
24 rue Lhomond, 75231 Paris Cedex 05 (France)
Fax : (+33)144-323-397
ꢀ
nected by a carbon carbon bond to the C30 position of the
hopane skeleton.[10–12]
The absolute configuration of the additional polyhydroxy
C5 side chain has been characterized by several analytical
and synthetic methods,[13] with the same d-ribitol configura-
tions having been found in the side chains of the glycoside 1
and the cyclopentyl ether 2, present in Zymomonas mobilis
(Figure 1),[14] as well as bacteriohopanetetrol (3), aminobac-
teriohopanetriol (4),[15] and adenosylhopane (6).[16] Biohopa-
noids that are hydroxylated at position 31, some of them
also bearing the cyclopentyl ether functionality (compounds
7–12, Figure 2), have also been isolated.[17–20]
E-mail: pierre.sinay@ens.fr
[b] Prof. S. P. Vincent
University of Namur, DØpartement de Chimie
Laboratoire de Chimie Bio-Organique, 61 rue de Bruxelles
5000 Namur (Belgium)
Fax : (+32)81-724-517
E-mail: stephane.vincent@fundp.ac.be
[c] Dr. W. Pan
Guizhou University
Center for Research and Development of Fine Chemicals
Guiyang, 550025 (P. R. China)
It is assumed that bacteriohopanetetrol (3) and some of
its polyol analogues would play the role of membrane stabil-
izers, although–-in view of the remarkable diversity of func-
tional groups bound to the C5 side chain—the biohopanoid
family may also serve other biological functions.[21] More-
over, the biosynthesis of some of these structures themselves
also addresses challenging questions.[22–24]
[d] Dr. W. Pan
Key Laboratory of Chemistry for Natural Products
of Guizhou Province, and Chinese Academy of Sciences
202 Sha-Chong South Road, Guiyang 550002 (P. R. China)
[e] Prof. G. Liang
Guiyang College of Traditional Chinese Medicine
Guiyang 550002 (P. R. China)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2007, 13, 1471 – 1480
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1471

essary that they are obtained
in pure form and sufficient
quantity. Since most of them
can only be isolated in trace
amounts from natural sources,
a general synthetic approach
would be of great interest.
The chemical synthesis of
such complex hopanoids had
been attempted earlier,[13,28,29]
but many synthetic difficulties
were encountered, and only
partially resolved. To date,
there is no general synthetic
strategy to achieve the prepa-
ration of the whole biohopa-
noid family.
Figure 1. Biohopanoids.
Biosynthetically, it is be-
lieved that all these structures
arise from the coupling of the
C
30 hopanic skeleton to an ap-
propriate side chain such as a
d-ribose We
derivative.[23]
therefore focused on a conven-
ient and potentially biomimetic
route to the synthesis of hopa-
noids through a (C30+C5) cou-
pling for the construction of
Figure 2. Biohopanoids hydroxylated at position C31.
the key intermediate: bacterio-
hopanetetrol (3)[14] or ribosyl-
hopane (5). In a preliminary
A preliminary feeding experiment using deuterated 6,6’-
[D2]-GlcNAc showed that the glycoside 1 and the ether 2
share the same GlcNAc-derived biosynthetic pathway,[24]
and so it was suggested that the biosynthesis of ether 2
should involve an unprecedented enzymatic ring contrac-
tion, transforming acetal 1 into ether 2. Such an enzymatic
reaction might also be invoked for the so far unknown bio-
synthetic pathways of such polyhydroxylated cyclopentyl
ethers as calditol,[25] crasserides,[26a] isocrasserides,[26b] and
keruffarides.[27]
communication we recently presented the direct halogen/
copper exchange on bromohopane 16 that ultimately led us
to complete the synthesis of glucosamine–hopanoid 1.[14]
Here we present a more general metallation strategy for
the hopane skeleton:
a lithiation of phenylsulfide 14
(Scheme 1) that resulted in the formation of hopanyllithium
and hopanyl cuprates. This novel methodology allowed us to
synthesize polyols 1, 3, 5, and 31 (Figure 1) in a flexible way.
Both for the investigation of the biological functions of bi-
ohopanoids and for the study of their biosynthesis it is nec-
Results and Discussion
Many efforts have already been invested in order to synthe-
size ribosylhopane 5 (Scheme 4) and other naturally occur-
ring C35 hopanepolyols. The key coupling step has usually
been achieved through Wittig-type reactions between the
Abstract in Chinese:
C
30 hopane skeleton and an appropriate chiral building
block for the C5 side chain, but the Wittig couplings with d-
ribosides have always given poor yields (8–36%),[13,28,30] the
poor efficiencies of the couplings having been ascribed to
the steric hindrance of the bulky hopane skeleton. To date,
the best methodology for preparing bacteriohopanetetrol
(3) is a multistep (C30+C2+C3) sequence involving the asym-
metric construction of the ribitol subunit.[29]
To the best of our knowledge, no strategy based on the
use of nonstabilized organometallic hopane derivatives for
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Chem. Eur. J. 2007, 13, 1471 – 1480

Ribosyl–C30 Hopane Derivatives
FULL PAPER
project, since: i) the excellent
nucleophilicity of organo-
lithiums towards aldehydes
should allow us to synthesize
all biohopanoids shown in
Figures 1 and 2, and ii) orga-
nolithium species can be
transformed into organocup-
rates and then coupled to ep-
oxides to generate (in this
instance) hopanetetrol (3), a
key (bio)synthetic intermedi-
Scheme 1. 1) PhSSPh, PBu3 (90%). 2) I2, PPh3 (quant.). 3) and 4) see Table 1.
ꢀ
carbon carbon bond formation in the synthesis of ribosylho-
ate for a wide range of biohopanoids.
pane 5 or bacteriohopanetetrol 3 and their derivatives has
ever been explored. In fact, organometallic reagents are usu-
ally more efficient than Wittig reagents or sulfonyl deriva-
tives for reactions with aldehydes or epoxides, due to their
higher reactivities and lower steric demands in relation to
ylides. We therefore investigated the application of an orga-
nometal-mediated cross-coupling strategy to enable a direct
(C30+C5) route to C35 hopanepolyols and their derivatives.
Halogen/metal exchange having been unsuccessful, we in-
vestigated arene-mediated reductive lithiation procedures
using LiDBB (lithium 4,4’-di-tert-butylbiphenylide).[33,34]
The most significant application of LiDBB is for the
ꢀ
cleavage of C S bonds in phenyl sulfides, which is extremely
efficient and has proven very useful for the syntheses of
complex natural products such as erythromycin.[35,36]
Reductive lithiation ofthe hopane derivatives : We therefore
investigated the reductive lithiation of 29-phenylthiohopane
14 or iodohopane 15 and their coupling with riboside 17 ac-
cording to Cohenꢁs procedure (Scheme 1).[34]
Application of the published procedure gave the desired
coupling products 20, but in disappointing low yield, the ex-
periments resulting either in the incomplete reduction of the
phenylsulfide to give hopanyllithium or in the total protona-
tion of the generated hopanyllithium to give hopane 23
(Scheme 1). Through the use of larger amounts of DBB and
Li the yields were improved to 40 and 24% (Table 1, en-
Generation ofHopanyllithium : We first attempted numer-
ous standard methods for the generation of the organome-
tallic species—organolithium, -magnesium, and -zinc re-
agents—most commonly used to activate the bulky C30
hopane skeleton. To assess whether the metalated hopane
had been formed, we used aldehydes 17,[31] 18,[32] and 19,1
derived from d-ribose (Scheme 1), for the cross-coupling re-
actions. Unfortunately though, classical Grignard or Barbier
halogen/metal exchanges with Mg, Zn, or Li failed to give
the desired hopanyl–metal species from iodohopane 15 or
bromohopane 16, which could
be easily prepared from known
Table 1. Coupling experiments involving a LiDBB-promoted lithiation of sulphide 14 and iodide 15 (see
hopanol 13 (Scheme 1).[29] If
the halogenides 15 and 16
were used for the metallation,
the only product we were able
to detect and isolate was the
protonation product 23, and so
we reasoned that the metallat-
ed hopane intermediate was
probably unstable and would
have to be generated by a
quick and efficient procedure
and then engaged in a coupling
reaction as quickly as possible.
We considered that the gen-
Scheme 1).
Entry Substrate RCHO
[equiv][a]
DBB
(equiv)
Li
t
Yield
[%][b]
Side product
[%][c]
Procedure[d]
[equiv] [h]
1
2
3
4
5
6
7
14
14
14
15
15
14
14
17 (3)
17 (2)
17 (2)
17 (4)
17 (3)
18 (2.5)
19 (2)
6
4
6
6
6
6
5
4
3
6
4
4
6
5
2.5
0.5
1
0.7
0.7
2
40
70
81
24
40
12
8
60
25
19
N
I
I
N
I
I
47[e]
24[e]
86
2.5
90
I
[a] Numbers of equivalents were calculated on the basis of starting hopanoid 14 or 15. [b] Isolated yields.
[c] From sulfide 14 the only competing reaction is a protonation yielding 23. [d] N (normal addition sequence):
sulfide 14 was added to the LiDBB solution. I (inversed addition sequence): LiDBB was slowly added to sul-
fide 14 or iodide 15. [e] From iodide 15 two side products were observed: 23, from a protonation, and 24, from
an elimination (in both cases, the ratio 23/24 4:1 was observed).
eration of
a hopanyllithium
species was a key issue for this
tries 1 and 4), starting from sulfide 14 and iodide 15, respec-
1
Aldehyde 19 was prepared from a known ribitol derivative[14] by stan-
dard procedures.
tively. In all cases we isolated 50–60% of the protonation
byproduct 23 when the addition sequence proposed by
Cohen et al.[34] was followed.
Much to our delight, though, an excellent yield of the de-
sired coupling product was finally obtained when the addi-
tion order of the reactants was reversed (Table 1, entries 2
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1473

S. P. Vincent, P. Sinaþ et al.
and 3): Instead of the addition of phenylsulfide 14 into a
THF solution of LiDBB radical anion, the freshly prepared
LiDBB was added dropwise to the solution of phenylsulfide
14 in dry THF at ꢀ788C. Coupling yields of up to 81%
were reproducibly obtained (Table 1, entry 3).
In the same optimized procedure, hopane halides 15 and
16 gave significantly lower yields: no more than 40% of the
desired alcohol 20, together with large amounts of hopane
23 and diploptene 24 as byproducts (Table 1, entry 5).
Surprisingly, the use of other aldehydes such as 18 and 19
under the same optimized conditions also resulted only in
very low yields (Table 1, entries 6 and 7).
It was essential for us to establish this absolute configura-
tion, since this protected ribosylhopane 20 can potentially
be converted into naturally occurring biohopanoids possess-
ing an additional hydroxy group at C31, such as the hopane-
pentols 7 or 8 or the aminobacteriohopanetetrols 11 or 12
(Figure 2).
Synthesis ofhopanepentol : Natural bacteriohopanepentols
have been detected in eubacteria: Zhao et al.,[17] for in-
stance, reported the isolation and tentative structural deter-
mination of the two bacteriohopanepentols 7 and 8 from
Nostoc PCC 6720 (Figure 2), while bacteriohopanepentols
have also been found as subunits linked to polyhydroxylated
cyclopentitol moieties (compounds 9 and 10),[18,19] although
the stereochemical patterns of the side chains have not been
clearly established in the latter two cases. Most of the poly-
ols that have been investigated up to now probably possess
the same configuration as bacteriohopanetetrol 3, but with
an additional stereochemical center at positions C31 or even
C30. Consequently, the synthesis of these hopanepentols
should demonstrate their absolute configurations and pro-
vide new tools for the investigation of their biosynthesis and
their biological functions.
Determination ofthe absolute conifgurations : The two re-
sulting epimeric alcohols (R)-20 and (S)-20, obtained in a
1
ratio of 7:1 (determined by H NMR), could easily be sepa-
rated as benzoates 25 and 26 (Scheme 2). Removal of the
benzoyl groups gave back the two pure diastereoisomers
(R)-20 and (S)-20 (Scheme 2).
It was anticipated that it might be possible to engage the
newly formed secondary alcohol in an intramolecular aceta-
lation, giving rise to a pyranoside. NMR data of pyranosides
are very characteristic and well documented, thus potential-
ly allowing us, by comparison, to determine the relative and
absolute configurations of newly formed stereogenic centers.
Indeed, compound (R)-20 was hydrolyzed under acidic
conditions to afford (after peracetylation) the pyranoside 28
(Scheme 2). Depending on the configuration at C31, the
hopane–pyranoside 28 might exhibit either a d-allose or an
l-talose stereochemical pattern, and this could be easily dif-
ferentiated by analyzing the coupling constants between
The pentaacetylbacteriohopanepentol 32 (Scheme 3) thus
became one of our synthetic targets, as it could reasonably
be derived from (R)-20. The direct reduction of 27 to the
corresponding pentitol 31, followed by a peracetylation, re-
1
protons H31 and H32. The H NMR spectrum of 28 gave a
JH31,H32 coupling constant of 10.2 Hz, which unambiguously
demonstrated that these two protons were in a 1,2-trans-dia-
xial relationship and implying that peracetate 28 possesses
the same configurations as d-allose, which could be con-
firmed by comparison with the NMR data for d-allose per-
acetate.[37] Since NMR data proved that the two diastereo-
isomers are epimeric at position C31, the additional hydroxy
group in (R)-20 is R-configured, while that in (S)-20 is S-
configured (Scheme 2).
Scheme 3. 1) H2SO4, acetone, 08C!RT (92%). 2) NaBH4, THF/EtOH,
RT (96%). 3) HCl (conc.), THF/MeOH, RT. 4) pyr, Ac2O (90%, two
steps).
sulted in an unsatisfactory
yield. Interestingly, though,
acetalation of glycolipid 27 re-
gioselectively gave the monop-
rotected acetonide 29, which
was readily reduced to the triol
30 in high yield. This triol was
readily deprotected and pera-
cetylated to give the desired
pentaacetate 32 in 22% overall
yield in 10 steps from a com-
mercially available hopanone
(Scheme 3). This compound
should also serve as a key tool
to demonstrate the absolute
Scheme 2. 1) BzCl, py (96%). 2) MeONa/MeOH (quant.). 3) HCl, THF/dioxane, 708C . 4) A2cO, pyr (95%,
two steps).
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Ribosyl–C30 Hopane Derivatives
FULL PAPER
configurations of natural hopanepolyols such as 9 and 10
(Figure 2).
In a previous work we had described the direct transfor-
mation of bromide 16 into an organocopper species3 and its
coupling to epoxide 36 (Scheme 5).[14]
Deoxygenation and reduction of20 : For the preparation of
ribosylhopane (5) or derivatives such as bacteriohopanete-
trol (3), aminotriol 4, or glycoside 1, the epimeric mixture
20 was deoxygenated at position 31 (Scheme 4) via the xan-
thate 33. Subsequent homolytic reduction afforded the de-
sired deoxygenated product 34 in 95% yield.
The previously described LiDBB reductive lithiation of
phenylsulfide 14 offered us the opportunity to generate ho-
panyl cuprates. Instead of homocuprates (dialkyl cuprates),
we developed a procedure for the preparation of a hopa-
nylthienyl mixed cuprate based on Lipshutzꢁs methodolo-
gy.[39,40] Thienylalkyl cuprates are readily prepared from 2-
thienyllithium and copper(I)
cyanide and they only transfer
the alkyl group: in our case,
one equivalent of hopane phe-
nylsulfide 14 was therefore
necessary. Moreover, mixed
cuprates are inherently more
stable than dialkyl cuprates
Scheme 4. 1) CS2, LiHMDS, then MeI (xanthate 33). 2) nBu3SnH (95%, two steps). 3) HCl, THF/dioxane.
4) pyr, Ac2O (92%, two steps).
and their reactivities towards
other substrates are similar to
those of other cuprates.
After optimization, triace-
tate 35 was obtained in 92%
yield from methyl riboside 34
and was found to be analytical-
ly identical to the previously
synthesized
compound.[28,29]
This is a key target compound
as it can easily be transformed
into ribosylhopane (5), which
is regarded as a potential bio-
synthetic intermediate for bio-
hopanoids such as 1, 3, 4, or 6
Scheme 5.
(Figure 1).[21,38] In this work, the triacetate 35 has been ob-
tained in nine steps and in 30% overall yield from a natural
hopanone, having previously been synthesized in much
lower overall yields through Wittig-type coupling reactions.
The analytical data for triacetate 35 were identical to those
previously described by Rohmer et al.[16,28,29,38]2
Hopanylcuprate–ribose coupling: For the synthesis of bio-
hopanoids that are not hydroxylated at position 31 (all com-
pounds represented in Figure 1), the most straightforward
strategy is coupling between a hopanecopper species and an
epoxide derived from ribitol, such as 36 (Scheme 5).
After optimization, coupling of the cuprate derived from
sulfide 14 and epoxide 36[14] gave 37 in 55% yield. In com-
parison with the methodology implying a “zero-valent”[41]
organocopper intermediate, this procedure appeared more
convenient and easier to scale up. As demonstrated previ-
ously, hopanoid 37 could be transformed into bacteriohopa-
netetrol (4) and glycoside 1.[14] Another advantage of the
coupling via an organocuprate is that it requires only a two-
equivalent excess of epoxide, while the coupling through a
“zero-valent” organocopper species requires a minimum of
three equivalents of epoxide 36.
Conclusions
2
To provide further structural corroboration, we transformed the precur-
sor of triacetate 35 into the peracetate of bacteriohopanetetrol 3, which
has been very well characterized in the literature, and compared it with
the natural compound.[13,29]
In summary, we have developed a (C30+C5) methodology
based on the metallation of hopanyl sulfide 14 and its effi-
cient coupling either to an aldehyde or to an epoxide, both
derived from d-ribose. Since the metallated hopane was
found to undergo rapid protonation or degradation, the key
parameter for efficient coupling between the bulky hopane
skeleton and the electrophile was the rapid generation of a
hopanyllithium intermediate through a LiDBB reductive
lithiation. This novel strategy greatly improved the yield of
the hopane–ribose coupling reaction, which was regarded as
3
These organocopper species have been termed “zero-valent” in the lit-
erature,[41] although their chemical nature has never been clearly dem-
onstrated.
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S. P. Vincent, P. Sinaþ et al.
the most concise sequence for the syntheses of biohopa-
noids.
Thanks to this procedure, we achieved an efficient synthe-
sis of ribosylhopane 5 in an overall yield of 28% in nine
steps from a commercial hopanone. We also showed that
natural hopane pentol derivatives (Figure 2) could also be
prepared by this sequence. Finally, we showed that the ho-
panyllithium intermediate could also be efficiently trans-
formed into a mixed cuprate, thus allowing an even more
direct synthesis of biohopanoids that are not hydroxylated
at position C31 (Figure 1).
We have already taken advantage of this sequence to pre-
pare natural hopanoids 1,[14] 3,[14] and 5 (Scheme 4) in suffi-
cient amounts to explore both their biosyntheses and their
biological functions.
was purified by FCC (2,2,4-trimethylpentane/EtOAc 15:1) to give 14 as a
white powder (12.0 mg, 90%). Rf = 0.75 (cyclohexane/EtOAc 3:1); m.p.
203.5–2048C ; a[]D23
=
+93 (c
=
1.0 in CH3Cl); 1H NMR (400 MHz,
CDCl3): d = 7.38–7.17 (m, 5H; H arom.), 3.20 (ABX, J
AHCTREUNG
J
J
U
=
12.2 Hz, 1H; H30b), 2.61 (ABX,
J
U
=
ACHTREUNG
Me), 1.00, 0.98 (2”s, 6H; 8b- and 14a-Me), 0.89 (s, 3H; 4a-Me), 0.86 (s,
3H; 10b-Me), 0.84 (s, 3H; 4b-Me), 0.70 (s, 3H; 18a-Me), 1.13–1.95 (m,
25H; H hopane), 0.73–0.97 ppm (m, 3H; H hopane); 13CNMR
(101 MHz, CDCl3): d = 137.8, 129.0, 128.7, 125.5, 56.1 (C5), 54.5 (C17),
50.4 (C9), 49.3 (C13), 45.7 (C21), 44.3 (C18), 42.1 (C3), 41.8 (C14), 41.6
(C8), 41.5 (C19), 41.2 (C30), 40.3 (C1), 37.41 (C22), 37.4 (C10), 33.6
(C15), 33.4 (C24), 33.3, 33.2 (C4, C7), 27.8 (C20), 24.0 (C12), 22.8 (C16),
21.6 (C23), 20.9 (C11), 20.2 (C29), 18.7 (C2, C6), 16.6, 16.5 (C26, C27),
15.9 (C25), 15.7 ppm (C28); MS (DCI-NH3): m/z: 521 [M+H]+; HRMS:
m/z: calcd for C36H57S: 521.4181; found: 521.4175.
It is now possible to envision the synthesis of various bac-
teriohopanepolyols, both naturally occurring and modified,
with potential biological applications.
30-Iodohopane (15): Compound 13[29] (300 mg, 0.7 mmol) was dissolved
under argon in anhydrous toluene (30 mL), PPh3 (1.83 g, 7.0 mmol), imi-
dazole (476 mg, 7.0 mmol), and I2 (1.42 g, 5.6 mmol) were then succes-
sively added to the reaction mixture, and it was then stirred at 808Cfor
2 h. The resulting mixture was allowed to cool to room temperature,
after which it was treated with saturated aqueous Na2S2O3 solution
(40 mL). The aqueous phase was then extracted twice with excess CH2Cl2
and the combined organic phases were washed with brine, dried over
MgSO4, and filtered through cotton. The solvents were evaporated under
reduced pressure, and subsequent FCC purification (2,2,4-trimethylpen-
Experimental Section
Materials and procedure: All chemicals were purchased from Acros,
Sigma, Aldrich, or Fluka and were used without further purification. Tet-
rahydrofuran, diethyl ether, and toluene were freshly distilled over
sodium benzophenone, dichloromethane over P2O5. 1H and 13CNMR
spectra were recorded with Bruker AC250 and DRX 400 spectrometers.
All compounds were characterized by 1H and 13CNMR, as well as by
1H–1H and H–13Ccorrelation experiments. 13Cshift values of the carbon
1
atoms in the hopanoid skeleton did not significantly depend on the na-
tures of the side chains. Mass spectra were recorded in the electron
impact (EI), chemical ionization (CI), or Fast Atom Bombardment
(FAB) modes on a JMS-700 spectrometer. Specific optical rotations were
measured with a Perkin–Elmer 241 polarimeter in a 1 dm cell. Melting
points were determined with a Büchi B-535 apparatus. Column chroma-
tography was performed on silica gel (Kieselgel Si 60) (40–63 mm). Alco-
hol 13 was prepared from the commercially available Dammar resin
(Sigma–Aldrich), in four steps, by known procedures.[29]
tane) afforded 15 as a white powder (377 mg, quantitative yield). Rf
0.60 (2,2,4-trimethylpentane); m.p. 220–2218C ; [a]2D3 = +67 (c = 0.9 in
CHCl3); 1H NMR (400 MHz, CDCl3): d = 3.36 (ABX, J
(22,30b) = 2.5,
(30a,30b) = 9.5 Hz, 1H; H30b), 3.24 (ABX, J(22,30a) = 5.7, J(30a,30b)
= 9.5 Hz, 1H; H30a), 1.08 (d, J(22,29) = 6.2 Hz, 3H; 22-Me), 0.99 (s,
=
AHCTREUNG
J
N
G
ACHTREUNG
AHCTREUNG
6H; 8b-, 14a-Me), 0.89 (s, 3H; 4a-Me), 0.86 (s, 3H; 10b-Me), 0.83 (s,
3H; 4b-Me), 0.74 (s, 3H; 18a-Me), 1.11–1.98 (m, 25H; H hopane), 0.73–
1.01 ppm (m, 3H; H hopane); 13CNMR (101 MHz, CDCl 3): d = 56.2
(C5), 54.2 (C17), 50.5 (C9), 49.3 (C13), 44.6 (C18), 44.2 (C21), 43.5
(C30), 42.1 (C3), 41.7 (C14), 41.8 (C8), 41.5 (C19), 40.4 (C1), 37.8 (C22),
37.4 (C10), 33.6 (C15), 33.4 (C24), 33.3 (C4, C7), 27.3 (C20), 24.0 (C12),
22.9 (C16), 21.6 (C23), 20.9 (C11), 21.0 (C29), 18.7 (C2, C6), 16.6, 16.5
(C26, C27), 15.9 (C25), 15.8 ppm (C28); MS (CI-CH4): m/z (%): 411
(100) [MꢀI].
Moisture-sensitive ribosyl–hopane coupling reactions: All the coupling
reactions were conducted under argon in flame- or oven-dried glass,
cooled under a stream of argon or in a dessicator in the presence of
P2O5. Solvents were dried just before their use. All transfers (reagents in
solution and solvents) were carried out with oven-dried needle or cannu-
la. Argon was dried by passing it successively through a tube filled with
CaCl2 and a gas drying bottle filled with KOH.
30-Bromohopane (16): Compound 13[29] (129 mg, 0.3 mmol) was dissolved
under argon in anhydrous toluene (20 mL), PPh3 (782 mg, 3.0 mmol), imi-
dazole (204 mg, 3.0 mmol), and Br2 (1.62 g, 1.8 mmol) were then succes-
sively added to the reaction mixture, and it was stirred at 808Cfor 2 h.
The resulting mixture was allowed to cool to room temperature, after
which it was treated with saturated aqueous Na2S2O3 solution (30 mL).
The aqueous phase was then extracted twice with excess CH2Cl2, the
combined organic phased were washed with brine, dried over MgSO4,
and filtered through cotton, and the solvents were evaporated under re-
duced pressure. FCC purification (2,2,4-trimethylpentane) afforded 16 as
a white powder (143 mg, 97%). Rf = 0.55 (2,2,4-trimethylpentane); m.p.
LiDBB preparation: Freshly prepared Li (20.0 mg, 2.9 mmol) and DBB
(480.0 mg, 1.8 mmol) were added under argon to freshly distilled THF
(5 mL). The flask was then clamped in an ultrasonic bath at a maximum
energy position and the irradiation was continued for 2 min at 08Cto
afford a blue solution. The reaction mixture was stirred for 10 min at 08C
and was then sonicated again for 2 min. This procedure was repeated
four times over 1 h to generate a dark blue solution of LiDBB.
Atom and position numberings: We systematically numbered the
C30 pentacyclic hopane skeleton and the C5 ribitol side chain according to
literature data.[42,43]
214.5–2168C ; a[]D23
CDCl3): d = 3.52 (ABX, J
H30b), 3.43 (ABX, J(22,30a) = 6.9, J
1.14 (d, J(22,29) = 6.2 Hz, 3H; 22-Me), 0.99 (s, 6H; 8b-, 14a-Me), 0.89
=
+55 (c
(22,30b) = 2.5, J
(30a,30b) = 9.8 Hz, 1H; H30a),
=
1.0 in CHCl3); 1H NMR (400 MHz,
30-Phenylthiohopane (14): Tri-n-butylphosphine (82.4 mL, 0.3 mmol) was
G
ACHTREUNG
added under argon to
a
solution of hopan-30-ol 13[29] (11.0 mg,
A
ACHTREUNG
0.03 mmol) in dry pyridine (1 mL), followed by phenyl disulfide (33.6 mg,
0.2 mmol), and the reaction mixture was stirred overnight at room tem-
perature. The mixture was then diluted with excess CH2Cl2 and washed
with aqueous HCl (1m), NaOH (3m), and brine, the combined organic
phases were dried over MgSO4 and filtered through cotton, and the sol-
vents were concentrated to dryness to afford a crude yellow oil, which
ACHTREUNG
(s, 3H; 4a-Me), 0.86 (s, 3H; 10b-Me), 0.83 (s, 3H; 4b-Me), 0.75 (s, 3H;
18a-Me), 1.13–1.98 (m, 25H; H hopane), 0.73–1.02 ppm (m, 3H; H ho-
pane); 13C NMR (101 MHz, CDCl3): d
= 56.1 (C5), 54.1 (C17), 50.4
(C9), 49.2 (C13), 44.5 (C18), 44.0 (C21), 43.3 (C30), 42.1 (C3), 41.8
(C14), 41.6 (C8), 41.5 (C19), 40.3 (C1), 38.6 (C22), 37.4 (C10), 33.6
1476
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1471 – 1480

Ribosyl–C30 Hopane Derivatives
FULL PAPER
(C15), 33.4 (C24), 33.2 (C4, C7), 27.3 (C20), 23.9 (C12), 22.7 (C16), 21.6
(C23), 20.9 (C11), 19.9 (C29), 18.7 (C2, C6), 16.6, 16.5 (C26, C27), 15.9
(C25), 15.8 ppm (C28); MS (EI): m/z (%): 490 (10) [M]+, 492 (10) [M]+,
369 (15) [cleavage between C21 and C22], 269, 271 (60) [Mꢀrings A, B,
and C], 191 (100) [rings A and B], cleavage; HRMS: m/z: calcd for
C30H51Br: 490.3171; found: 490.3174.
ACHTREUNG
1,4-Bis-O-benzyl-2,3-O-isopropylidene-5-aldehydo-d-ribitol (19): To a so-
lution of 5-O-(tert-butyldimethylsilyl)-2,3-O-isopropylidene-d-ribitol[14]
(226.0 mg, 0.737 mmol) in dry DMF (6 mL) was added NaH (60%,
53.1 mg, 2.21 mmol) in portions under argon at ꢀ788C. The suspension
was stirred at this temperature for 30 min, before BnBr (220 mL,
1.85 mmol) was added. The reaction mixture was allowed to gradually
warm up to ꢀ208Cand was then quenched at this temperature with
MeOH (1 mL), diluted with brine, and extracted with excess diethyl
ether. The combined organic phases were washed with brine, dried
(MgSO4), and filtered. After evaporation under reduced pressure, the re-
sulting crude product was purified by FCC purification (cyclohexane/
EtOAc 10:1) to yield the dibenzylated ribitol as a light yellow oil
(245.1 mg, 69% yield). To a solution of this dibenzyl ether (132 mg,
0.271 mmol) in THF (8 mL) under argon was added TBAF (1m, 136 mL,
0.136 mmol) portionwise at room temperature. The reaction was stirred
overnight at this temperature and concentrated to dryness under reduced
pressure. The residue was purified by FCC purification (cyclohexane/
EtOAc 2:1) yielding the primary alcohol as a white solid (96 mg, 95%
yield). This alcohol was directly engaged in a Swern oxidation. Thus,
oxalyl chloride (26.5 mL, 0.31 mmol) was added to a stirred solution of
dry DMSO (45.6 mL, 0.643 mmol) in freshly distilled CH2Cl2 (3 mL)
under argon at ꢀ788C. The resulting mixture was stirred for 10 min. A
solution of the alcohol (96 mg, 0.257 mmol) in distilled CH2Cl2 (3 mL)
was then added under argon. After 15 min at ꢀ788C, the reaction was
quenched with dry Et3N (180 mL, 1.28 mmol) and the mixture was al-
lowed to gradually warm up to room temperature. Water (5 mL) was
added, and the mixture was extracted three times with CH2Cl2. The com-
bined organic extracts were washed successively with HCl (1m), saturated
aqueous NaHCO3 and brine, and dried over MgSO4. After filtration, the
solvents were evaporated under reduced pressure and the residue was
purified by FCC purification (cyclohexane/EtOAc 5:1) yielding aldehyde
19 as a white solid (88.6 mg, 93%). Rf = 0.45 (cyclohexane/EtOAc 3:1);
m.p. 100-1018C ; [a]2D0 = +2 (c = 0.61 in CHCl3); 1H NMR (400 MHz,
H33), 4.17 (d, J = 1.5 Hz, 1H; H32), 3.78 (m, 1H; H31), 3.55 (d, J
OH) = 1.3 Hz, 1H; OH-31), 3.46 (s, 3H; OMe), 1.51, 1.36 (2”s, 6H;
acetal-Me), 1.02 (d, J(22,29) = 5.6 Hz, 3H; 22-Me), 0.98 (s, 6H; 8b- and
(31,31-
AHCTREUNG
14a-Me), 0.87 (s, 3H; 4a-Me), 0.84 (s, 3H; 10b-Me), 0.82 (s, 3H; 4b-Me),
0.77 (s, 3H; 18a-Me), 1.10–1.90 (m, 27H; H hopane), 0.71–0.98 ppm (m,
3H; H hopane); 13CNMR (101 MHz, CDCl 3): d
=
111.9 (Cq acetal),
109.9 (C35), 92.9 (C32), 85.9 (C33), 80.1 (C34), 69.4 (C31), 56.1 (C5),
55.6 (OMe), 54.6 (C17), 50.4 (C9), 49.3 (C13), 46.7 (C21), 44.2 (C18),
42.1 (C3), 41.7 (C14), 41.6 (C8), 41.55 (C19), 40.3 (C1), 39.2 (C30), 37.3
(C10), 34.0 (C22), 33.7 (C15), 33.4 (C24), 33.2 (C4, C7), 28.1 (C20), 26.3,
24.7 (acetal-Me), 23.9 (C12), 23.0 (C16), 21.6 (C23), 20.9 (C11), 19.8
(C29), 18.6 (C2, C6), 16.5, 16.4 (C26, C27), 15.9 (C28), 15.86 ppm (C25);
MS (DCI-NH3): m/z: 632 [M+NH4]+; HRMS
(DCI): m/z: calcd for
T
C39H70O5N: 632.5254; found: 632.5250.
AHCTREUNG
EtOAc 6:1); m.p. 221–222.58C ; a[]D22
= +19 (c = 0.5 in CHCl3);
1H NMR (400 MHz, CDCl3): d = 4.99 (s, 1H; H35), 4.88 (d, J = 6.0 Hz,
1H; H34), 4.62 (d, J = 6.0 Hz, 1H; H33), 4.43 (d, J = 2.4 Hz, 1H; H32),
3.86 (m, 1H; H31), 3.49 (s, 3H; OMe), 3.32 (d, J
ACHTREUNG
1H; OH-31), 1.53, 1.35 (2”s, 6H; acetal-Me), 1.02 (d, J
AHCTREUNG
3H; 22-Me), 0.99 (s, 6H; 8b-, 14a-Me), 0.88 (s, 3H; 4a-Me), 0.85 (s, 3H;
10b-Me), 0.83 (s, 3H; 4b-Me), 0.77 (s, 3H; 18a-Me), 1.13–1.90 (m, 27H;
H hopane), 0.73–0.97 ppm (m, 3H; H hopane); 13CNMR (101 MHz,
CDCl3): d = 111.9 (Cq acetal), 110.5 (C35), 89.0 (C32), 85.7 (C33), 82.8
(C34), 70.4 (C31), 56.1 (C5), 55.9 (OMe), 54.5 (C17), 50.4 (C9), 49.3
(C13), 46.9 (C21), 44.3 (C18), 42.1 (C3), 41.8 (C14), 41.7 (C8), 41.6
(C19), 40.6 (C30), 40.3 (C1), 37.4 (C10), 34.7 (C22), 33.7 (C15), 33.4
(C24), 33.3, 33.2 (C4, C7), 27.9 (C20), 26.3, 24.6 (acetal-Me), 24.0 (C12),
22.9 (C16), 21.6 (C23), 21.0 (C11), 20.4 (C29), 18.7 (C2, C6), 16.6, 16.5
(C26, C27), 16.0 (C28), 15.9 ppm (C25); MS (DCI-NH3): m/z: 632
[M+NH4]+; HRMS: m/z: calcd for C39H70O5N: 632.5254; found:
632.5240.
CDCl3): d = 9.68 (d, J
4.41–4.63 (m, 4H; BnCH2), 4.48 (m, 1H; H2), 4.40 (dd, J
(3,4) = 6.5 Hz, 1H; H3), 3.97 (dd, J(3,4) = 6.5, J(4,5) = 2.7 Hz, 1H;
H5b), 3.79 (dd, J(1b,2) = 4.2 Hz, J(1a,1b) = 10.3 Hz, 1H; H1b), 3.55
(dd, J(1a,2) = 6.9 Hz, J(1a,1b) = 10.3 Hz, 1H; H1a), 1.52, 1.50 ppm (2”
ACHTREUNG
AHCTREUNG
A
N
ACHTREUNG
A
ACHTREUNG
A
ACHTREUNG
s, 6H; acetal-Me); 13CNMR (101 MHz): d = 200.4 (C5), 137.7, 136.6,
128.5, 128.4, 128.3, 128.2, 127.8, 127.7, 109.6 (Cq acetal), 81.4 (C4), 76.4
(C2), 75.4 (C3), 73.5, 72.8 ppm (PhCH 2), 68.1 (C1), 27.4, 25.2 ppm
(acetal-Me); MS (DCI-NH3): m/z: 388 [M+NH4]+; HRMS: m/z: calcd
for C22H30O5N: 388.2124; found: 388.2118.
Benzoates 25 and 26: Benzoyl chloride (45.5 mL, 0.4 mmol) was added
dropwise under argon at 08Cto a solution of the mixture of ( R)-20 and
(S)-20 (30.0 mg, 0.05 mmol) in dry pyridine (3 mL). The reaction mixture
was stirred at room temperature for 24 h, quenched with saturated aque-
ous NaHCO3, and extracted three times with CH2Cl2, the combined ex-
tracts were washed with brine and dried (MgSO4), and the solvents were
removed to dryness under reduced pressure. The resulting mixture was
separated by FCC (cyclohexane/EtOAc 20:1) to yield 25 (29.4 mg, 85%);
Rf = 0.32 (cyclohexane/EtOAc 15:1); and 26 (4.0 mg, 11%); Rf = 0.37
(cyclohexane/EtOAc 15:1).
Compound 25: [a]2D1 = ꢀ23 (c = 1.1 in CHCl3); 1H NMR (400 MHz,
CDCl3): d = 8.08–7.46 (m, 5H; H arom.), 5.38 (m, 1H; H31), 4.99 (s,
1H; H35), 4.77 (d, J = 6.0 Hz, 1H; H33), 4.65 (d, J = 6.0 Hz, 1H; H34),
4.22 (d, J = 8.4 Hz, 1H; H32), 3.36 (s, 3H; OMe), 1.51, 1.32 (2”s, 6H;
31-Hydroxy-ribosylhopane (20): The LiDBB solution was prepared by
the general procedure (Li 2.9 mmol; DBB 1.9 mmol; THF 5 mL) and
was slowly transferred (over 20 minutes) by glass syringe into a solution
of phenylthiohopane 14 (238.0 mg, 0.5 mmol) in freshly distilled THF
(11 mL) under argon at ꢀ788C. After this time the dark blue color of the
reaction mixture remained unchanged. The mixture was stirred at ꢀ788C
for 3 min, and a solution of aldehyde 17[31] (220.0 mg, 1.1 mmol) in anhy-
drous THF (1 mL) was then added dropwise at ꢀ788Cover a period of
5 min. After stirring at ꢀ788Cfor 10 min, the reaction mixture was al-
lowed to warm up gradually to room temperature and stirring was con-
tinued overnight. The reaction mixture was quenched with aqueous
NH4Cl solution, the aqueous phase was extracted three times with
CH2Cl2, the combined organic extracts were washed with brine, dried
(MgSO4), and filtered through cotton, and the solvents were evaporated
under reduced pressure. The resulting crude product was purified by
FCC (cyclohexane/EtOAc 15:1) to yield 20 as a 7:1 mixture of the two
epimers (R)-20 and (S)-20 (225.0 mg, 81% overall yield); Rf = 0.42 (cy-
clohexane/EtOAc 6:1); and hopane 23 (36.0 mg, 19%); Rf = 0.81 (n-
pentane). The analyses of pure (R)-20 and (S)-20 are described below.
acetal-Me), 1.04 (d, J(22,29) = 6.6 Hz, 3H; 22-Me), 0.96, 0.88 (2”s, 6H;
A
8b-, 14a-Me), 0.87 (s, 3H; 4a-Me), 0.83 (s, 3H; 10b-Me), 0.81 (s, 3H; 4b-
Me), 0.49 (s, 3H; 18a-Me), 1.08–1.90 (m, 27H; H hopane), 0.69–0.95 ppm
(m, 3H; H hopane); 13C NMR (101 MHz, CDCl3): d = 166.2 (PhC=O),
133.0, 130.1, 129.6, 128.3, 112.3 (Cq acetal), 110.1 (C35), 88.8 (C32), 85.3
(C34), 81.4 (C33), 71.9 (C31), 56.1 (C5), 55.8 (OMe), 54.5 (C17), 50.4
(C9), 49.3 (C13), 46.4 (C21), 44.2 (C18), 42.1 (C3), 41.7 (C14), 41.6 (C8),
41.5 (C19), 40.3 (C1), 38.8 (C30), 37.3 (C10), 33.7 (C15), 33.6 (C22), 33.4
(C24), 33.2 (C4, C7), 28.2 (C20), 26.5, 25.0 (acetal-Me), 24.0 (C12), 22.8
(C16), 21.6 (C23), 20.9 (C11), 20.0 (C29), 18.6 (C2, C6), 16.5, 16.3 (C26,
Chem. Eur. J. 2007, 13, 1471 – 1480
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1477

S. P. Vincent, P. Sinaþ et al.
C27), 15.9 (C25), 15.6 ppm (C28); MS (DCI-NH3): m/z: 736 [M+NH4]+;
HRMS: m/z: calcd for C46H74O6N: 736.5516; found: 736.5515.
dryness to afford the crude pyranosylhopanetetrol 27. The resulting mix-
ture was dried overnight under vacuum before being suspended at room
temperature in a mixture of dry acetone (3 mL) and THF (3 mL) con-
taining a catalytic amount of concentrated sulfuric acid (10 mL). The re-
action mixture was stirred at room temperature for 16 h, neutralized with
solid NaHCO3, and filtered through cotton. The filtrates were concentrat-
ed to dryness and the residue was purified by FCC (cyclohexane/EtOAc
4:1) to afford 29 as a syrup (18.2 mg, 92%). Rf = 0.52 (cyclohexane/
EtOAc 2:1). Compound 29 was characterized as its peracetate.
Compound 26: [a]D21
CDCl3): d = 8.23–7.49 (m, 5H; H arom.), 5.30 (m, 1H; H31), 5.09 (s,
=
ꢀ9 (c = 0.5 in CHCl3); 1H NMR (400 MHz,
1H; H35), 4.66 (dd, J
(d, J(33,34) = 6.0 Hz, 1H; H34), 4.49 (dd, J
1.0 Hz, 1H; H32), 3.47 (s, 3H; OMe), 1.54, 1.31 (2”s, 6H; acetal-Me),
1.12 (d, J(22,29) = 6.2 Hz, 3H; 22-Me), 0.98 (2”s, 6H; 8b-, 14a-Me),
A
ACHTREUNG
A
N
ACHTREUNG
ACHTREUNG
0.88 (s, 3H; 4a-Me), 0.85 (s, 3H; 10b-Me), 0.83 (s, 3H; 4b-Me), 0.78 (s,
3H; 18a-Me), 1.15–1.90 (m, 27H; H hopane), 0.72–0.97 ppm (m, 3H;
31,35-Di-O-acetyl-d-ribosylhopane (peracetate-29): Ac2O (1 mL) was
added to a solution of 29 (18.2 mg, 0.03 mmol) in pyridine (2 mL). The
reaction mixture was stirred overnight at room temperature, after which
it was poured into a mixture of ice/water. The resulting mixture was then
extracted three times with CH2Cl2, and the combined organic phases
were washed with brine, dried (MgSO4), and filtered through cotton. The
solvents were removed under reduced pressure and the resulting residue
was purified by FCC (cyclohexane/EtOAc 6:1) to yield the peracetate of
29 as a white powder (20.4 mg, 97%). Rf = 0.53 (cyclohexane/EtOAc
2:1); [a]1D8 = +13 (c = 1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d =
H hopane); 13CNMR (101 MHz, CDCl 3): d
= 166.0 (PhC=O), 133.0,
130.4, 129.9, 128.4, 112.4 (Cq acetal), 110.6 (C35), 86.6 (C32), 85.9 (C34),
82.1 (C33), 73.9 (C31), 56.1 (C5), 55.3 (OMe), 54.5 (C17), 50.4 (C9), 49.3
(C13), 46.9 (C21), 44.3 (C18), 42.1 (C3), 41.8 (C14), 41.7 (C8), 41.5
(C19), 40.3 (C1), 37.4 (C10), 36.9 (C30), 34.4 (C22), 33.7 (C15), 33.4
(C24), 33.2, 32.9 (C4, C7), 27.9 (C20), 26.7, 25.0 (acetal-Me), 24.0 (C12),
22.8 (C16), 21.6 (C23), 21.0 (C11), 20.5 (C29), 18.7 (C2, C6), 16.6, 16.5
(C26, C27), 15.94 (C25), 15.89 ppm (C28); MS (DCI-NH3): m/z: 736
[M+NH4]+; HRMS: m/z: calcd for C46H74O6N: 736.5516; found:
736.5518.
6.22 (s, 1H; H35), 5.09 (ddd, J
8.2 Hz, 1H; H31), 4.73 (d, J
(33,34) = 6.0 Hz, 1H; H33), 4.16 (d, J
2.09 (2”s, 6H; 2 Ac), 1.52, 1.36 (2”s, 6H; acetal-Me), 0.98 (d, J
A
G
E
=
N
=
32,33,34,35-Tetra-O-acetyl-d-allopyranosylhopane (28):
A solution of
J
A
ACHTREUNG
(R)-20 (45.0 mg, 0.07 mmol) in mixture of THF (1 mL), dioxane
a
ACHTREUNG
(1 mL), and HCl (1m, 1 mL) was heated at reflux at 708Cfor 4.5 h. The
reaction mixture was then quenched with pyridine at 708Cand concen-
trated to dryness to afford the crude tetrol, which was acetylated (1 mL
Ac2O/pyr, 1:2) overnight at room temperature and purified by FCC (cy-
clohexane/acetone 20:1) to yield 28b (34.0 mg, 64% yield, Rf 0.36 with
= 5.9 Hz, 3H; 22-Me), 0.97 (2”s, 6H; 8b-, 14a-Me), 0.88 (s, 3H; 4a-
Me), 0.84 (s, 3H; 10b-Me), 0.81 (s, 3H; 4b-Me), 0.70 (s, 3H; 18a-Me),
1.11–1.90 (m, 27H; hopane), 0.72–0.98 ppm (m, 3H; hopane); 13CNMR
(101 MHz, CDCl3): d = 170.7, 169.4 (2”CH3C=O), 113.0 (Cq acetal),
102.5 (C35), 89.4 (C32), 85.2 (C34), 81.3 (C33), 71.0 (C31), 56.1 (C5),
54.4 (C17), 50.4 (C9), 49.3 (C13), 46.2 (C21), 44.3 (C18), 42.1 (C3), 41.8
(C14), 41.6 (C8), 41.5 (C19), 40.3 (C1), 38.3 (C30), 37.4 (C10), 33.7
(C15), 33.2 (C22), 33.4 (C24), 33.2 (C4, C7), 28.1 (C20), 26.5, 25.1
(acetal-Me), 23.9 (C12), 22.9 (C16), 21.6 (C23), 21.2, 21.0 (2”CH3C=O),
20.9 (C11), 20.0 (C29), 18.7 (C2, C6), 16.5, 16.4 (C26, C27), 15.9 ppm
(C25, C28); MS (DCI-NH3): m/z: 702 [M+NH4]+; HRMS: m/z: calcd for
C42H72O7N: 702.5309; found: 702.5311.
cyclohexane/acetone 5:1) and 28a as a white solid (13.0 mg, 24%). Rf
=
0.35 (cyclohexane/acetone 5:1).
Compound 28b: m.p. 239–2408C ; a[]D22
1H NMR (400 MHz, CDCl3): d = 5.93 (d, J
5.69 (t, J(32,33) = J(33,34) = 3.0 Hz, 1H; H33), 4.98 (dd, J
3.0, J(34,35) = 8.7 Hz, 1H; H34), 4.73 (dd, J(31,32) = 10.2, J
3.0 Hz, 1H; H32), 3.98 (dt, J(30a,31) = 1.6, J(30b,31) = J(31,32)
10.2 Hz, 1H; H31), 2.20, 2.13, 2.05, 2.04 (4”s, 12H; AcO), 1.00 (d,
(22,29) = 5.3 Hz, 3H; 22-Me), 0.98 (s, 6H; 8b-, 14a-Me), 0.88 (s, 3H;
=
+59 (c
(34,35) = 8.7 Hz, 1H; H35),
(33,34) =
(32,33) =
= 1.7 in CHCl3);
AHCTREUNG
A
N
ACHTREUNG
C
A
ACHTREUNG
A
G
A
=
33,34-O-Isopropylidene-hopanepentol (30): NaBH4 (1.5 mg, 0.04 mmol)
was added to a solution of 29 (16.0 mg, 0.03 mmol) in a mixture of THF
(1 mL) and EtOH (1 mL) and the mixture was stirred overnight at room
temperature, quenched with acetone (0.5 mL), and concentrated to dry-
ness to afford 30 as a white solid (15.7 mg, 96%). Rf = 0.15 (cyclohex-
ane/EtOAc 2:1). Compound 30 was characterized as its peracetate.
J
ACHTREUNG
4a-Me), 0.84 (s, 3H; 10b-Me), 0.82 (s, 3H; 4b-Me), 0.70 (s, 3H; 18a-Me),
1.01–1.80 (m, 27H; H hopane), 0.71–0.93 ppm (m, 3H; H hopane);
13CNMR (101 MHz, CDCl 3): d = 170.0, 169.4, 169.3, 169.1 (4”CH3C=
O), 90.1 (C35), 70.6 (C31), 70.0 (C32), 68.6 (C33), 68.4 (C34), 56.1 (C5),
54.5 (C17), 50.4 (C9), 49.3 (C13), 46.3 (C21), 44.2 (C18), 42.1 (C3), 41.8
(C14), 41.6 (C8), 41.5 (C19), 40.3 (C1), 37.7 (C30), 37.4 (C10), 33.7
(C15), 33.4 (C24), 33.26, 33.22 (C4, C7), 33.1 (C22), 27.9 (C20), 23.9
(C12), 22.9 (C16), 21.6 (C23), 20.9 (C11), 20.87, 20.7, 20.6, 20.5 (4”
CH3C=O), 20.3 (C29), 18.7 (C2, C6), 16.6, 16.5 (C26, C27), 15.9 (C25),
15.6 ppm (C28); MS (DCI-NH3): m/z: 746 [M+NH4]+; HRMS: m/z:
calcd for C43H72O9N: 746.5207; found: 746.5194.
33,34-O-Isopropylidene-31,32,35-tri-O-acetyl-hopanepentol (peracetate-
30): Triol 30 (19.0 mg, 0.03 mmol) was acetylated overnight at room tem-
perature in Ac2O/pyr (1:1, 2 mL), the crude mixture was concentrated to
dryness under reduced pressure, and the resulting product was purified
by FCC (cyclohexane/acetone 20:1) to afford the triacetate as a colorless
syrup (21.8 mg, 95%). Rf = 0.51 (cyclohexane/acetone 5:1); [a]2D5 = +32
(c = 1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d = 5.28 (m, 1H;
Compound 28a: 1H NMR (400 MHz, CDCl3): d = 6.23 (d, J
4.0 Hz, 1H; H35), 5.65 (t, J = 3.1 Hz, 1H; H33), 5.12 (dd, J
3.0, J(34,35) = 4.0 Hz, 1H; H34), 4.78 (dd, J(31,32) = 10.1, J
3.1 Hz, 1H; H32), 4.23 (dt, J(30a,31) = 1.8, J(30b,31) = J(31,32)
10.1 Hz, 1H; H31), 2.20, 2.17, 2.06, 2.04 (4”s, 12H; AcO), 0.99 (2”s,
6H; 8b-, 14a-Me), 0.96 (d, J(22,29) = 5.6 Hz, 3H; 22-Me), 0.88 (s, 3H;
ACHTREUNG
H31), 5.24 (dd, J
1H; H34), 4.31 (ABX, J
H35b), 4.22 (dd, J(32,33) = 9.4, J
1H; H35a), 2.12, 2.11, 2.03 (3”s, 9H; 3”Ac), 1.57, 1.40 (2”s, 6H;
acetal-Me), 0.99 (s, 6H; 8b-, 14a-Me), 0.97 (d, J(22,29) = 4.3 Hz, 3H;
A
ACHTREUNG
AHCTREUNG
A
=
A
=
A
N
ACHTREUNG
A
ACHTREUNG
A
G
A
=
AHCTREUNG
AHCTREUNG
22-Me), 0.88 (s, 3H; 4a-Me), 0.85 (s, 3H; 10b-Me), 0.83 (s, 3H; 4b-Me),
0.73 (s, 3H; 18a-Me), 1.08–1.96 (m, 27H; H hopane), 0.73–0.97 ppm (m,
3H; H hopane); 13C NMR (101 MHz, CDCl3): d = 170.71, 170.68, 169.7
(3”CH3C=O), 109.6 (Cq acetal), 75.5 (C34), 74.3 (C33), 71.2 (C31), 70.5
(C32), 62.1 (C35), 56.1 (C5), 54.5 (C17), 50.4 (C9), 49.3 (C13), 46.4
(C21), 44.3 (C18), 42.1 (C3), 41.8 (C14), 41.7 (C8), 41.5 (C19), 40.3 (C1),
37.4 (C10), 33.9 (C30), 33.7 (C22), 33.6 (C15), 33.4 (C24), 33.3, 33.2 (C4,
C7), 27.9 (C20), 27.8, 25.7 (acetal-Me), 24.0 (C12), 22.8 (C16), 21.6
(C23), 20.93 (C11), 21.0, 20.89, 20.83 (3”CH3C=O), 19.9 (C29), 18.7 (C2,
C6), 16.6, 16.5 (C26, C27), 15.9, 15.8 ppm (C25, C28); MS (DCI-NH3):
4a-Me), 0.85 (s, 3H; 10b-Me), 0.83 (s, 3H; 4b-Me), 0.73 (s, 3H; 18a-Me),
1.00–1.80 (m, 27H; H hopane), 0.69–0.95 ppm (m, 3H; H hopane);
13CNMR (101 MHz, CDCl 3): d = 170.2, 169.4, 169.3, 169.1 (4”CH3C=
O), 88.4 (C35), 69.7 (C31), 67.3 (C32), 66.3 (C33), 64.6 (C34), 56.1 (C5),
54.6 (C17), 50.4 (C9), 49.3 (C13), 46.6 (C21), 44.3 (C18), 42.1 (C3), 41.8
(C14), 41.7 (C8), 41.5 (C19), 40.3 (C1), 37.4 (C10), 36.9 (C30), 33.7
(C15), 33.4 (C24), 33.3, 33.2 (C4, C7), 32.6 (C22), 27.6 (C20), 24.0 (C12),
22.9 (C16), 21.6 (C23), 20.94 (C11), 20.92, 20.8, 20.7, 20.5 (4”CH3C=O),
19.5 (C29), 18.7 (C2, C6), 16.6, 16.5 (C26, C27), 15.9 (C25), 15.8 ppm
(C28); MS (DCI-NH3): m/z: 746 [M+NH4]+; HRMS: m/z: calcd for
C43H72O9N: 746.5207; found: 746.5201.
m/z: 746 [M+NH4]+; HRMS
ACHTREUNG
found: 746.5558.
33,34-O-Isopropylidene-d-allopyranosylhopane (29): A solution of (R)-20
(22.0 mg, 0.03 mmol) in a mixture of THF (1.2 mL), dioxane (0.75 mL),
and HCl (1m, 0.75 mL) was heated at reflux at 708Cfor 5 h. The reaction
mixture was then quenched with pyridine at 708C, and concentrated to
(31R,32R,33S,34S)-31,32,33,34,35-Penta-O-acetyl-hopanepentol
33,34-O-Isopropylidene-hopanepentol (30, 15.7 mg, 0.03 mmol) was dis-
solved at 08Cin THF/MeOH (1:1, 2 mL) containing a catalytic amount
1478
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1471 – 1480

Ribosyl–C30 Hopane Derivatives
FULL PAPER
of concentrated aqueous HCl (37%, 12 mL). The resulting mixture was
vigorously stirred overnight at room temperature and then neutralized
with solid NaHCO3 and filtered through cotton, and the filtrates were
concentrated. The resulting crude pentol 31 was acetylated overnight at
room temperature in Ac2O/pyr (1:1, 2 mL) and the resulting mixture was
purified by FCC (cyclohexane/EtOAc 4:1) to provide the hopanepentol
pentacetate 32 as a white solid (18.1 mg, 90% yield in two steps from
(C13), 46.2 (C21), 44.4 (C18), 42.1 (C3), 41.8 (C14), 41.7 (C8), 41.6
(C19), 40.3 (C1), 37.4 (C10), 36.8 (C22), 33.7 (C15), 33.4 (C24), 33.3, 33.2
(C4, C7), 32.5 (C30), 32.0 (C20), 27.8 (C31), 26.5, 25.1 (acetal-Me), 24.0
(C12), 22.9 (C16), 21.6 (C23), 21.0 (C11), 20.0 (C29), 18.7 (C2, C6), 16.6,
16.5 (C26, C27), 15.9 ppm (C25, C28); MS (DCI-NH3): m/z: 616
[M+NH4]+; HRMS: m/z: calcd for C39H70O4N: 616.5305; found:
616.5303.
30). M.p. 158–1598C ; a[]D19
(400 MHz, CDCl3): d = 5.38–5.32 (m, 2H; H33, H34), 5.26 (dd, J
3.7, (32,33) 6.6 Hz, 1H; H32), 5.14 (ddd, (30a,31)
(30b,31) = 11.3, J(31,32) = 3.7 Hz, 1H; H31), 4.40 (ABX, J(34,35b) =
3.2, J(35a,35b) 12.2 Hz, 1H; H35b), 4.16 (ABX, J(34,35a) 7.2,
(35a,35b) = 12.2 Hz, 1H; H35a), 2.15, 2.13, 2.11, 2.08, 2.06 (5”s, 15H;
5 Ac), 0.98, 0.96 (2”s, 6H; 8b-, 14a-Me), 0.94 (d, J(22,29) = 6.3 Hz, 3H;
=
+24 (c
=
0.8 in CHCl3); 1H NMR
(31,32)
1.5,
Ribosylhopane (35): A solution of compound 34 (20.5 mg, 0.03 mmol) in
a mixture of THF (1.5 mL), dioxane (0.75 mL), and HCl (1m, 0.75 mL)
was heated at reflux at 758Cfor 4.5 h. The reaction mixture was then
quenched with pyridine at 758C, and concentrated to dryness to afford
the crude ribosylhopane 5. To this residue was added pyridine (2 mL, fol-
lowed by Ac2O (1 mL). The reaction mixture was stirred at room temper-
ature, after which it was poured into a mixture of ice/water and extracted
three times with CH2Cl2, and the combined organic phases were washed
with brine, dried (MgSO4), and filtered through cotton. The solvents
were removed under reduced pressure and the resulting residue was puri-
fied by FCC (cyclohexane/EtOAc 15:1) to yield 35a (15.7 mg, 68%); Rf
= 0.57 (cyclohexane/acetone 6:1) and 35b (6.0 mg, 26%); Rf = 0.51 (cy-
clohexane/acetone 6:1). These two compounds have been described in
the literature previously.[16,28,29,38]
AHCTREUNG
=
J
A
=
J
A
=
J
N
G
ACHTREUNG
A
=
A
=
J
ACHTREUNG
AHCTREUNG
22-Me), 0.88 (s, 3H; 4a-Me), 0.84 (s, 3H; 10b-Me), 0.82 (s, 3H; 4b-Me),
0.70 (s, 3H; 18a-Me), 1.00–1.90 (m, 27H; H hopane), 0.72–0.90 ppm (m,
3H; H hopane); 13C NMR (101 MHz, CDCl3): d = 170.6, 170.5, 170.0,
169.7, 169.5 (5”CH3C=O), 71.6 (C32), 70.0 (C34), 69.8 (C31), 69.4 (C33),
61.7 (C35), 56.1 (C5), 54.4 (C17), 50.4 (C9), 49.3 (C13), 46.2 (C21), 44.3
(C18), 42.1 (C3), 41.8 (C14), 41.6 (C8), 41.5 (C19), 40.3 (C1), 37.4 (C10),
35.5 (C30), 33.69 (C22), 33.66 (C15), 33.4 (C24), 33.2 (C4, C7), 28.0
(C20), 23.9 (C12), 22.9 (C16), 21.6 (C23), 20.9 (C11), 20.8, 20.7, 20.6 (5”
CH3C=O), 19.9 (C29), 18.7 (C2, C6), 16.5, 16.4 (C26, C27), 15.9 (C25),
15.8 ppm (C28); MS (DCI-NH3): m/z: 790 [M+NH4]+; HRMS: m/z:
calcd for C45H76O10N: 790.5469; found: 790.5472.
33,34-O-Isopropylidene-35-O-benzylhopanetetrol (37)
Solution A (lithium 2-thienylcyanocuprate): nBuLi (2.5m in hexane,
0.46 mL, 1.2 mmol) was added dropwise under argon at ꢀ788Cto a solu-
tion of thiophene (92 mL, 1.2 mmol) in dry THF (2 mL). Stirring was con-
tinued at this temperature for 15 min and then at ꢀ208Cfor 30 min. This
solution was transferred into a slurry of CuCN (103.0 mg, 1.2 mmol) and
dry THF (0.5 mL) at ꢀ788C, and the suspended mixture was then al-
lowed to warm to ꢀ408C, giving a clear, light tan solution.
31-O-(S-Methyldithiocarbonyl)-ribosylhopane (33): LiHMDS (97%,
33.4 mg, 0.2 mmol) was added under argon at ꢀ788Cto a solution of
(R)-20 (41.0 mg, 0.07 mmol) in anhydrous THF (4 mL), followed by
carbon disulfide (12 mL, 0.2 mmol). Stirring was continued at this temper-
ature for 3 h, and methyl iodide (33.3 mL, 0.5 mmol) was then added at
ꢀ788C. The reaction mixture was stirred at this temperature for a further
30 min and then at room temperature overnight. The mixture was
quenched with water (4 mL) and extracted twice with CH2Cl2, and the or-
ganic layer was washed with brine, dried over MgSO4, filtered through
cotton, and concentrated in vacuo. Further purification by FCC (cyclo-
hexane/EtOAc 40:1) provided 33 as a white solid (54.0 mg, quantitative
yield). Rf = 0.44 (toluene/EtOAc 40:1); m.p. 167–168.58C ; a[ ]2D3 = +6
Solution B (LiDBB): LiDBB was prepared by the general procedure,
with Li (12.0 mg, 1.7 mmol) and DBB (345.3 mg, 1.3 mmol) in THF
(4 mL).
Solution C: The LiDBB solution (B) was slowly (over
a period of
10 min) transferred under argon at ꢀ788Cinto a solution of phenylthio-
hopane 14 (150.0 mg, 0.3 mmol) in THF (10 mL). Lithium 2-thienylcya-
nocuprate (1.6 mL of Solution A) was then added dropwise to the reac-
tion mixture at ꢀ788Cover a period of 5 min by glass syringe, after
which a solution of epoxide 36[14] (190.0 mg, 0.7 mmol) in THF (1 mL)
was added. After having been stirred at ꢀ788Cfor 10 min, the reaction
mixture was allowed to warm to room temperature over 1 h and the stir-
ring was continued overnight. The reaction was quenched with aqueous
NH4Cl solution, the aqueous phase was extracted three times with excess
CH2Cl2, the combined extracts were washed with brine, dried (MgSO4),
and filtered through cotton, and the solvents were evaporated under re-
duced pressure. The resulting crude mixture was purified by FCC (2,2,4-
trimethylpentane/acetone 40:1!30:1) to yield 37 as a white powder
(106.4 mg, 55%), Rf = 0.30 (2,2,4-trimethylpentane/acetone 15:1) and
hopane 23 (42.0 mg, 36%), Rf = 0.81 (cyclohexane). Analytical data for
37 matched those published.[14]
(c = 0.8 in CHCl3); 1H NMR (400 MHz, CDCl3): d
= 6.02 (m, 1H;
H31), 4.99 (s, 1H; H35), 4.78 (d, J = 6.0 Hz, 1H; H34), 4.62 (d, J =
6.0 Hz, 1H; H33), 4.21 (d, J = 9.0 Hz, 1H; H32), 3.40 (s, 3H; OMe),
2.60 (s, 3H; SMe), 1.51, 1.34 (2”s, 6H; acetal-Me), 1.01 (d, J(22,29) =
N
5.7 Hz, 3H; 22-Me), 0.97 (2”s, 6H; 8b-, 14a-Me), 0.88 (s, 3H; 4a-Me),
0.85 (s, 3H; 10b-Me), 0.82 (s, 3H; 4b-Me), 0.70 (s, 3H; 18a-Me), 1.12–
1.97 (m, 27H; H hopane), 0.72–0.97 ppm (m, 3H; H hopane); 13CNMR
(101 MHz, CDCl3): d = 112.4 (Cq acetal), 110.2 (C35), 88.0 (C32), 85.2
(C34), 81.2 (C33), 80.5 (C31), 56.1 (C5), 56.0 (OMe), 54.5 (C17), 50.4
(C9), 49.4 (C13), 46.4 (C21), 44.2 (C18), 42.1 (C3), 41.74 (C14), 41.68
(C8), 41.6 (C19), 40.3 (C1), 39.1 (C30), 37.4 (C10), 33.7 (C15), 33.5
(C22), 33.4 (C24), 33.3, 33.2 (C4, C7), 28.4 (C20), 26.9, 26.5, 25.1 (acetal-
Me), 24.0 (C12), 22.9 (C16), 21.6 (C23), 20.9 (C11), 20.3 (C29), 19.0
(SMe), 18.7 (C2, C6), 16.6, 16.4 (C26, C27), 15.9 (C25), 15.7 ppm (C28);
MS (DCI-NH3): m/z: 722 [M+NH4]+; HRMS: m/z: calcd for
C41H72O5S2N: 722.4852; found: 722.4871.
33,34-O-Isopropylidene-35-O-methyl-b-d-ribosylhopane (34): nBu3SnH
(97%, 0.3 mL, 1.1 mmol) was added under dry argon to a solution of
xanthate 33 (99.0 mg, 0.14 mmol) in freshly distilled toluene (5 mL), fol-
lowed by a catalytic amount of AIBN (5.0 mg), and the mixture was
heated at reflux overnight at 808C. The reaction mixture was then con-
centrated to dryness to afford a residue, which was purified by FCC (cy-
Acknowledgements
This work was supported by the Centre National de la Recherche Scienti-
fique (CNRS), by the Association Franco-Chinoise pour la Recherche
Scientifique et Technique (AFCRST, program PRA B02-07), by the
French embassy in China (Ph.D. grant to W.P.), and by the China Schol-
arship Council (Research Fellowships for Young Scientists to C.S.).
clohexane/EtOAc 20:1) to yield 34 as a white solid (83.0 mg, 98%). Rf
=
0.38 (toluene/EtOAc 40:1); m.p. 179.7–1808C ; a[ ]2D3 = +32 (c = 1.0 in
CHCl3); 1H NMR (400 MHz, CDCl3): d = 4.97 (s, 1H; H35), 4.63 (d, J
= 6.0 Hz, 1H; H34), 4.54 (d, J = 6.0 Hz, 1H; H33), 4.13 (m, 1H; H32),
3.38 (s, 3H; OMe), 1.52, 1.35 (2”s, 6H; acetal-Me), 0.99 (s, 6H; 8b-,
14a-Me), 0.97 (d, J
A
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Received: May 10, 2006
Published online: November 20, 2006
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